Submissions for variant NM_001378615.1(CC2D2A):c.4179+1del

dbSNP: rs386833760

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
UW Hindbrain Malformation Research Program, University of Washington	RCV000194003	SCV000256339	pathogenic	Joubert syndrome 9	2015-02-23	criteria provided, single submitter	research
Eurofins Ntd Llc (ga)	RCV000725911	SCV000701189	pathogenic	not provided	2016-03-14	criteria provided, single submitter	clinical testing
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV000626744	SCV000747447	pathogenic	Clubfoot; Encephalocele; Polydactyly, postaxial, type A1; Polycystic kidney disease; Oligohydramnios; Microcephaly; Narrow chest	2017-01-01	criteria provided, single submitter	clinical testing
Invitae	RCV000696362	SCV000824920	pathogenic	Familial aplasia of the vermis; Meckel-Gruber syndrome	2024-01-22	criteria provided, single submitter	clinical testing	This sequence change affects a splice site in intron 33 of the CC2D2A gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in CC2D2A are known to be pathogenic (PMID: 19777577). This variant is present in population databases (rs386833761, gnomAD 0.09%). Disruption of this splice site has been observed in individual(s) with Joubert and/or Meckel-Gruber syndrome (PMID: 19777577, 26092869). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as c.4179del. ClinVar contains an entry for this variant (Variation ID: 56312). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV000194003	SCV001367954	pathogenic	Joubert syndrome 9	2016-01-01	criteria provided, single submitter	clinical testing	This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PVS1,PS1,PM2,PP4.
Genetics Institute, Tel Aviv Sourasky Medical Center	RCV001391272	SCV001593223	pathogenic	Anencephaly; Polydactyly; Renal cyst	2021-05-12	criteria provided, single submitter	clinical testing
GeneDx	RCV000725911	SCV002512803	pathogenic	not provided	2022-04-27	criteria provided, single submitter	clinical testing	Canonical splice site variant expected to result in aberrant splicing, although in the absence of functional evidence the actual effect of this sequence change is unknown.; This variant is associated with the following publications: (PMID: 31589614, 33486889, 19777577, 26092869, 19466712)
Fulgent Genetics, Fulgent Genetics	RCV002490623	SCV002775236	pathogenic	Meckel syndrome, type 6; Joubert syndrome 9; COACH syndrome 2; Retinitis pigmentosa 93	2022-02-14	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002514253	SCV003744286	pathogenic	Inborn genetic diseases	2021-12-16	criteria provided, single submitter	clinical testing	The c.4179+1delG variant results from a deletion of one nucleotide at position c.4179+1 and involves the canonical splice donor site after coding exon 31 of the CC2D2A gene. Alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. Based on data from gnomAD, the - allele has an overall frequency of 0.01% (23/247170) total alleles studied. The highest observed frequency was 0.09% (9/9980) of Ashkenazi Jewish alleles. This mutation has been identified in 2 compound heterozygous individuals with Joubert syndrome as well as 2 compound heterozygous fetuses with Meckel syndrome (Mougou-Zerelli, 2009; Tallila, 2009; Bachmann-Gagescu, 2015). Based on the available evidence, this alteration is classified as pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000049724	SCV004803948	pathogenic	Meckel syndrome, type 6	2024-01-29	criteria provided, single submitter	clinical testing	Variant summary: CC2D2A c.4179+1delG is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Three predict the variant abolishes a canonical 5' splicing donor site, and two predict the variant creates a cryptic 5' donor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 9.3e-05 in 247170 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in CC2D2A causing Meckel Syndrome Type 6 (9.3e-05 vs 0.0011), allowing no conclusion about variant significance. c.4179+1delG has been reported in the literature in individuals affected with Meckel Syndrome or Joubert Syndrome (Mougou-Zerelli_2009, Tallila_2009, Bachmann-Gagescu_2015). These data indicate that the variant is likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 19777577, 19466712, 26092869). ClinVar contains an entry for this variant (Variation ID: 56312). Based on the evidence outlined above, the variant was classified as pathogenic.
Juha Muilu Group; Institute for Molecular Medicine Finland (FIMM)	RCV000049724	SCV000082131	probable-pathogenic	Meckel syndrome, type 6		no assertion criteria provided	not provided	Converted during submission to Likely pathogenic.
Juha Muilu Group; Institute for Molecular Medicine Finland (FIMM)	RCV000049724	SCV000082132	probable-pathogenic	Meckel syndrome, type 6		no assertion criteria provided	not provided	Converted during submission to Likely pathogenic.
Genetic Services Laboratory, University of Chicago	RCV002464102	SCV000593890	pathogenic	Meckel-Gruber syndrome	2014-09-22	no assertion criteria provided	clinical testing