Submissions for variant NM_001164508.2(NEB):c.8189A>G (p.Asp2730Gly)

gnomAD frequency: 0.00646  dbSNP: rs76767949

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000117772	SCV000231438	benign	not specified	2015-02-13	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV000117772	SCV000307393	benign	not specified		criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001081243	SCV000416959	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	RCV000117772	SCV000519884	benign	not specified	2016-05-18	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.
Invitae	RCV001081243	SCV000640870	benign	Nemaline myopathy 2	2024-01-31	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000588859	SCV000697840	benign	not provided	2017-04-24	criteria provided, single submitter	clinical testing	Variant summary: The NEB c.8189A>G (p.Asp2730Gly) variant involves the alteration of a conserved nucleotide, resulting in a missense substitution in a nebulin repeat domain (InterPro). 3/4 in silico tools predict a damaging outcome for this variant (SNPs&GO not captured due to low reliability index). 4/5 splice prediction tools predict creation of a de novo splice donor site and ESE finder predicts that this variant may introduce an SRp40 ESE site. However, these predictions have yet to be confirmed by functional studies. This variant was found in large control database ExAC in 970 of 97172 control chromosomes (27 homozygotes) of all ethnicities, but was predominantly observed in the East Asian subpopulation at a frequency of 0.091978 (649/7056 [25 homozygotes]). This frequency is about 26 times the estimated maximal expected allele frequency of a pathogenic NEB variant (0.0035355), providing strong evidence that this is likely a benign polymorphism found primarily in the populations of East Asian origin. In addition, multiple clinical diagnostic laboratories/reputable databases have classified this variant as likely benign (2x in ClinVar) or benign (3x in ClinVar). Taken together, this variant is classified as benign.
Athena Diagnostics Inc	RCV000588859	SCV000842876	benign	not provided	2018-03-26	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000117772	SCV000152032	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.	RCV001081243	SCV001463532	benign	Nemaline myopathy 2	2020-09-16	no assertion criteria provided	clinical testing