rs6717213

chr2-151619616-C-T

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.10707G>A(p.Lys3569=) variant causes a synonymous change. The variant allele was found at a frequency of 0.0391 in 1,613,874 control chromosomes in the GnomAD database, including 3,640 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.084 (1073 hom., cov: 31)
  • Exomes 𝑓: 0.034 (2567 hom.)
• Consequence: NEB NM_001164507.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 4.97

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]

ACMG classification

Verdict is Benign. Variant got -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.23).
• BP6: Variant 2-151619616-C-T is Benign according to our data. Variant chr2-151619616-C-T is described in ClinVar as [Benign]. Clinvar id is 129762.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.206 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NEB	NM_001164507.2	c.10707G>A	p.Lys3569=	synonymous_variant	73/182	ENST00000427231.7
NEB	NM_001164508.2	c.10707G>A	p.Lys3569=	synonymous_variant	73/182	ENST00000397345.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NEB	ENST00000397345.8	c.10707G>A	p.Lys3569=	synonymous_variant	73/182	5	NM_001164508.2	P5
NEB	ENST00000427231.7	c.10707G>A	p.Lys3569=	synonymous_variant	73/182	5	NM_001164507.2	A2
NEB	ENST00000409198.5	c.9978G>A	p.Lys3326=	synonymous_variant	70/150	5

Frequencies

GnomAD3 genomes AF: 0.0834 AC: 12685 AN: 152090 Hom.: 1058 Cov.: 31

Gnomad AFR AF: 0.210

Gnomad AMI AF: 0.0625

Gnomad AMR AF: 0.0456

Gnomad ASJ AF: 0.0639

Gnomad EAS AF: 0.167

Gnomad SAS AF: 0.122

Gnomad FIN AF: 0.0165

Gnomad MID AF: 0.0411

Gnomad NFE AF: 0.0181

Gnomad OTH AF: 0.0778

GnomAD3 exomes AF: 0.0556 AC: 13836 AN: 248946 Hom.: 920 AF XY: 0.0561 AC XY: 7576 AN XY: 135026

Gnomad AFR exome AF: 0.218

Gnomad AMR exome AF: 0.0214

Gnomad ASJ exome AF: 0.0612

Gnomad EAS exome AF: 0.168

Gnomad SAS exome AF: 0.115

Gnomad FIN exome AF: 0.0153

Gnomad NFE exome AF: 0.0178

Gnomad OTH exome AF: 0.0409

GnomAD4 exome AF: 0.0344 AC: 50338 AN: 1461666 Hom.: 2567 Cov.: 33 AF XY: 0.0363 AC XY: 26422 AN XY: 727116

Gnomad4 AFR exome AF: 0.222

Gnomad4 AMR exome AF: 0.0239

Gnomad4 ASJ exome AF: 0.0640

Gnomad4 EAS exome AF: 0.166

Gnomad4 SAS exome AF: 0.112

Gnomad4 FIN exome AF: 0.0148

Gnomad4 NFE exome AF: 0.0177

Gnomad4 OTH exome AF: 0.0531

GnomAD4 genome AF: 0.0838 AC: 12756 AN: 152208 Hom.: 1073 Cov.: 31 AF XY: 0.0845 AC XY: 6290 AN XY: 74420

Gnomad4 AFR AF: 0.210

Gnomad4 AMR AF: 0.0455

Gnomad4 ASJ AF: 0.0639

Gnomad4 EAS AF: 0.167

Gnomad4 SAS AF: 0.123

Gnomad4 FIN AF: 0.0165

Gnomad4 NFE AF: 0.0181

Gnomad4 OTH AF: 0.0884

Alfa AF: 0.0361 Hom.: 635

Bravo AF: 0.0897

Asia WGS AF: 0.183 AC: 635 AN: 3478

EpiCase AF: 0.0183

EpiControl AF: 0.0211

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 19, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jan 13, 2015	p.Lys3569Lys in exon 73 of NEB: This variant is not expected to have clinical si gnificance because it does not alter an amino acid residue and is not located wi thin the splice consensus sequence. It has been identified in 19.7% (795/4026) o f African American chromosomes from a broad population by the NHLBI Exome Sequen cing Project (http://evs.gs.washington.edu/EVS; dbSNP rs6717213). -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
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. -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 18, 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. -

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	Invitae	Feb 01, 2024	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.23
Cadd	Benign	12
Dann	Benign	0.91

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs6717213; hg19: chr2-152476130; COSMIC: COSV51419744; COSMIC: COSV51419744;