Submissions for variant NM_001164508.2(NEB):c.20158-6A>G

dbSNP: rs1553715636

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000579107	SCV000681287	uncertain significance	not specified	2017-12-18	criteria provided, single submitter	clinical testing	A variant of uncertain significance has been identified in the NEB gene. The c.20158-6 A>G variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The c.20158-6 A>G variant is not observed in large population cohorts (Lek et al., 2016). Several in silico splice prediction models predict that c.20158-6 A>G creates a cryptic acceptor site which may supplant the natural acceptor site and lead to abnormal gene splicing. However, in the absence of RNA/functional studies, the actual effect of this sequence change in this individual is unknown. This nucleotide substitution occurs at a position that is not conserved. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
3billion	RCV002250662	SCV002521786	uncertain significance	Arthrogryposis multiplex congenita 6	2022-05-22	criteria provided, single submitter	clinical testing	The variant is not observed in the gnomAD v2.1.1 dataset. Splice region (3-8 bases of the intron) variant: see below. In silico tools predict the variant to alter splicing and produce an abnormal transcript (SpliceAI: 1.00). Therefore, this variant is classified as uncertain significanceaccording to the recommendation of ACMG/AMP guideline.
Baylor Genetics	RCV002250662	SCV004200233	pathogenic	Arthrogryposis multiplex congenita 6	2023-06-28	criteria provided, single submitter	clinical testing
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV005252970	SCV005907848	likely pathogenic	Nemaline myopathy	2025-03-04	criteria provided, single submitter	curation	The c.20158-6A>G variant in NEB has been reported, in the compound heterozygous state, in 1 individual with nemaline myopathy (PMID: 30467404), and has been identified in 0.007% (3/44668) of East Asian chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs1553715636). Although this variant has been seen in the general population in a heterozygous state, its frequency is low enough to be consistent with a recessive carrier frequency. This variant has also been reported in ClinVar (Variation ID: 489291) and has been interpreted as pathogenic by Baylor Genetics and a variant of uncertain significance by GeneDx, 3billion, and Natera, Inc. This variant is located in the 3’ splice region. Computational tools do suggest an impact to splicing. However, this information is not predictive enough to determine pathogenicity. RNAseq analysis performed on affected tissue shows alternate splicing in 2170/9477 reads. Loss of function of the NEB gene is an established disease mechanism in autosomal recessive nemaline myopathy. In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic for autosomal recessive nemaline myopathy. ACMG/AMP Criteria applied: PVS1_strong, PM2_supporting, PM3_supporting (Richards 2015).
Natera, Inc.	RCV001834828	SCV002084096	uncertain significance	Nemaline myopathy 2	2021-07-28	no assertion criteria provided	clinical testing