rs16830192

Positions:

• chr2-151541531-G-C

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BA1

The NM_001164507.2(NEB):​c.20598C>G​(p.Gly6866=) variant causes a synonymous change. The variant allele was found at a frequency of 0.0163 in 1,613,128 control chromosomes in the GnomAD database, including 1,327 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.042 (357 hom., cov: 32)
  • Exomes 𝑓: 0.014 (970 hom.)
• Consequence: NEB NM_001164507.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 5.76

Genes affected

NEB (HGNC:7720): (nebulin) This gene encodes nebulin, a giant protein component of the cytoskeletal matrix that coexists with the thick and thin filaments within the sarcomeres of skeletal muscle. In most vertebrates, nebulin accounts for 3 to 4% of the total myofibrillar protein. The encoded protein contains approximately 30-amino acid long modules that can be classified into 7 types and other repeated modules. Protein isoform sizes vary from 600 to 800 kD due to alternative splicing that is tissue-, species-,and developmental stage-specific. Of the 183 exons in the nebulin gene, at least 43 are alternatively spliced, although exons 143 and 144 are not found in the same transcript. Of the several thousand transcript variants predicted for nebulin, the RefSeq Project has decided to create three representative RefSeq records. Mutations in this gene are associated with recessive nemaline myopathy. [provided by RefSeq, Sep 2009]

LOC124906081 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.37).
• BP6: Variant 2-151541531-G-C is Benign according to our data. Variant chr2-151541531-G-C is described in ClinVar as [Benign]. Clinvar id is 129722.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-151541531-G-C is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.137 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NEB	NM_001164507.2	c.20598C>G	p.Gly6866=	synonymous_variant	136/182	ENST00000427231.7	NP_001157979.2
NEB	NM_001164508.2	c.20598C>G	p.Gly6866=	synonymous_variant	136/182	ENST00000397345.8	NP_001157980.2
LOC124906081	XR_007087266.1	n.3756G>C		non_coding_transcript_exon_variant	2/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NEB	ENST00000397345.8	c.20598C>G	p.Gly6866=	synonymous_variant	136/182	5	NM_001164508.2	ENSP00000380505	P5
NEB	ENST00000427231.7	c.20598C>G	p.Gly6866=	synonymous_variant	136/182	5	NM_001164507.2	ENSP00000416578	A2

Frequencies

GnomAD3 genomes AF: 0.0420 AC: 6382 AN: 152076 Hom.: 345 Cov.: 32

Gnomad AFR AF: 0.111

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0194

Gnomad ASJ AF: 0.0320

Gnomad EAS AF: 0.145

Gnomad SAS AF: 0.0748

Gnomad FIN AF: 0.0000943

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.00226

Gnomad OTH AF: 0.0431

GnomAD3 exomes AF: 0.0295 AC: 7338 AN: 248604 Hom.: 378 AF XY: 0.0299 AC XY: 4035 AN XY: 134854

Gnomad AFR exome AF: 0.113

Gnomad AMR exome AF: 0.00861

Gnomad ASJ exome AF: 0.0322

Gnomad EAS exome AF: 0.147

Gnomad SAS exome AF: 0.0641

Gnomad FIN exome AF: 0.000139

Gnomad NFE exome AF: 0.00228

Gnomad OTH exome AF: 0.0191

GnomAD4 exome AF: 0.0136 AC: 19798 AN: 1460934 Hom.: 970 Cov.: 30 AF XY: 0.0149 AC XY: 10825 AN XY: 726754

Gnomad4 AFR exome AF: 0.117

Gnomad4 AMR exome AF: 0.00899

Gnomad4 ASJ exome AF: 0.0324

Gnomad4 EAS exome AF: 0.137

Gnomad4 SAS exome AF: 0.0652

Gnomad4 FIN exome AF: 0.000356

Gnomad4 NFE exome AF: 0.00164

Gnomad4 OTH exome AF: 0.0272

GnomAD4 genome AF: 0.0422 AC: 6419 AN: 152194 Hom.: 357 Cov.: 32 AF XY: 0.0427 AC XY: 3181 AN XY: 74422

Gnomad4 AFR AF: 0.111

Gnomad4 AMR AF: 0.0193

Gnomad4 ASJ AF: 0.0320

Gnomad4 EAS AF: 0.145

Gnomad4 SAS AF: 0.0755

Gnomad4 FIN AF: 0.0000943

Gnomad4 NFE AF: 0.00226

Gnomad4 OTH AF: 0.0531

Alfa AF: 0.0153 Hom.: 32

Bravo AF: 0.0458

Asia WGS AF: 0.137 AC: 474 AN: 3478

EpiCase AF: 0.00377

EpiControl AF: 0.00321

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Nov 26, 2014	p.Gly6866Gly in exon 136 of NEB: This variant is not expected to have clinical s ignificance because it has been identified in 10.7% (421/3922) of African Americ an chromosomes by the NHLBI Exome Sequencing Project (http://evs.gs.washington.e du/EVS/; dbSNP rs16830192). -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 14, 2016	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. -
Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	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. -

Nemaline myopathy 2 Benign:3

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	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. -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

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- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.37
CADD	Benign	6.7
DANN	Benign	0.75

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs16830192; hg19: chr2-152398045; COSMIC: COSV51419688; COSMIC: COSV51419688;