Submissions for variant NM_002180.3(IGHMBP2):c.1756+4C>T

gnomAD frequency: 0.00003  dbSNP: rs778913429

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000548573	SCV000642321	uncertain significance	Autosomal recessive distal spinal muscular atrophy 1; Charcot-Marie-Tooth disease axonal type 2S	2022-10-18	criteria provided, single submitter	clinical testing	This sequence change falls in intron 12 of the IGHMBP2 gene. It does not directly change the encoded amino acid sequence of the IGHMBP2 protein. It affects a nucleotide within the consensus splice site. This variant is present in population databases (rs778913429, gnomAD 0.1%). This variant has not been reported in the literature in individuals affected with IGHMBP2-related conditions. ClinVar contains an entry for this variant (Variation ID: 466584). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant is not likely to affect RNA splicing. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
GeneDx	RCV000611337	SCV000727869	likely benign	not specified	2018-02-28	criteria provided, single submitter	clinical testing	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Mayo Clinic Laboratories, Mayo Clinic	RCV001509412	SCV001716108	uncertain significance	not provided	2020-01-13	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002413541	SCV002716585	uncertain significance	Inborn genetic diseases	2020-03-12	criteria provided, single submitter	clinical testing	The c.1756+4C>T intronic variant results from a C to T substitution 4 nucleotides after coding exon 12 in the IGHMBP2 gene. This nucleotide position is not well conserved in available vertebrate species. Using the BDGP and ESEfinder splice site prediction tools, this alteration is not predicted to have any significant effect on this splice donor site; however, direct evidence is unavailable. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.