Submissions for variant NM_001164508.2(NEB):c.19102-6C>T

gnomAD frequency: 0.03008  dbSNP: rs145127681

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
PreventionGenetics, part of Exact Sciences	RCV000117732	SCV000307275	benign	not specified		criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000554492	SCV000416892	benign	Nemaline myopathy 2	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.
GeneDx	RCV000117732	SCV000519543	benign	not specified	2016-02-11	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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000554492	SCV000640637	benign	Nemaline myopathy 2	2025-02-03	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000117732	SCV001821226	benign	not specified	2021-08-12	criteria provided, single submitter	clinical testing	Variant summary: NEB c.19102-6C>T alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 4/4 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.027 in 233910 control chromosomes, predominantly at a frequency of 0.036 within the Non-Finnish European subpopulation in the gnomAD database, including 68 homozygotes. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 10 fold of the estimated maximal expected allele frequency for a pathogenic variant in NEB causing Nemaline Myopathy 2 phenotype (0.0035), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. To our knowledge, no occurrence of c.19102-6C>T in individuals affected with Nemaline Myopathy 2 and no experimental evidence demonstrating its impact on protein function have been reported. Four ClinVar submitters (evaluation after 2014) cite the variant as benign. Based on the evidence outlined above, the variant was classified as benign.
Breakthrough Genomics, Breakthrough Genomics	RCV001573747	SCV005245941	benign	not provided		criteria provided, single submitter	not provided
Athena Diagnostics	RCV000117732	SCV005620961	benign	not specified	2024-01-11	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000117732	SCV000151983	likely benign	not specified		no assertion criteria provided	clinical testing	Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed.
Natera, Inc.	RCV000554492	SCV001453271	benign	Nemaline myopathy 2	2020-09-16	no assertion criteria provided	clinical testing
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV001573747	SCV001800062	likely benign	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000117732	SCV001931918	benign	not specified		no assertion criteria provided	clinical testing