rs13013209

Positions:

• chr2-151643935-C-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001164507.2(NEB):​c.7839G>C​(p.Lys2613Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.449 in 1,613,728 control chromosomes in the GnomAD database, including 170,389 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K2613H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.35 (11467 hom., cov: 31)
  • Exomes 𝑓: 0.46 (158922 hom.)
• Consequence: NEB NM_001164507.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 3.39

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0031203926).
• BP6: Variant 2-151643935-C-G is Benign according to our data. Variant chr2-151643935-C-G is described in ClinVar as [Benign]. Clinvar id is 95137.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-151643935-C-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.481 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NEB	NM_001164507.2	c.7839G>C	p.Lys2613Asn	missense_variant	57/182	ENST00000427231.7
NEB	NM_001164508.2	c.7839G>C	p.Lys2613Asn	missense_variant	57/182	ENST00000397345.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NEB	ENST00000397345.8	c.7839G>C	p.Lys2613Asn	missense_variant	57/182	5	NM_001164508.2	P5
NEB	ENST00000427231.7	c.7839G>C	p.Lys2613Asn	missense_variant	57/182	5	NM_001164507.2	A2
NEB	ENST00000409198.5	c.7839G>C	p.Lys2613Asn	missense_variant	57/150	5

Frequencies

GnomAD3 genomes AF: 0.351 AC: 53281 AN: 151906 Hom.: 11472 Cov.: 31

Gnomad AFR AF: 0.0921

Gnomad AMI AF: 0.453

Gnomad AMR AF: 0.393

Gnomad ASJ AF: 0.386

Gnomad EAS AF: 0.266

Gnomad SAS AF: 0.386

Gnomad FIN AF: 0.438

Gnomad MID AF: 0.351

Gnomad NFE AF: 0.485

Gnomad OTH AF: 0.366

GnomAD3 exomes AF: 0.420 AC: 104730 AN: 249250 Hom.: 23355 AF XY: 0.424 AC XY: 57323 AN XY: 135208

Gnomad AFR exome AF: 0.0824

Gnomad AMR exome AF: 0.463

Gnomad ASJ exome AF: 0.389

Gnomad EAS exome AF: 0.283

Gnomad SAS exome AF: 0.383

Gnomad FIN exome AF: 0.446

Gnomad NFE exome AF: 0.483

Gnomad OTH exome AF: 0.424

GnomAD4 exome AF: 0.459 AC: 671392 AN: 1461704 Hom.: 158922 Cov.: 118 AF XY: 0.458 AC XY: 332975 AN XY: 727132

Gnomad4 AFR exome AF: 0.0758

Gnomad4 AMR exome AF: 0.456

Gnomad4 ASJ exome AF: 0.388

Gnomad4 EAS exome AF: 0.274

Gnomad4 SAS exome AF: 0.387

Gnomad4 FIN exome AF: 0.448

Gnomad4 NFE exome AF: 0.488

Gnomad4 OTH exome AF: 0.422

GnomAD4 genome AF: 0.350 AC: 53268 AN: 152024 Hom.: 11467 Cov.: 31 AF XY: 0.350 AC XY: 25995 AN XY: 74284

Gnomad4 AFR AF: 0.0917

Gnomad4 AMR AF: 0.393

Gnomad4 ASJ AF: 0.386

Gnomad4 EAS AF: 0.266

Gnomad4 SAS AF: 0.386

Gnomad4 FIN AF: 0.438

Gnomad4 NFE AF: 0.486

Gnomad4 OTH AF: 0.362

Alfa AF: 0.440 Hom.: 5003

Bravo AF: 0.335

TwinsUK AF: 0.490 AC: 1816

ALSPAC AF: 0.486 AC: 1872

ESP6500AA AF: 0.0983 AC: 407

ESP6500EA AF: 0.474 AC: 3979

ExAC AF: 0.414 AC: 50104

Asia WGS AF: 0.283 AC: 988 AN: 3478

EpiCase AF: 0.479

EpiControl AF: 0.474

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

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	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Nov 26, 2014	p.Lys2613Asn in exon 57 of NEB: This variant is not expected to have clinical si gnificance because it has been identified in 47% (3979/8400) of European America n chromosomes by the NHLBI Exome Sequencing Project (http://evs.gs.washington.ed u/EVS/; dbSNP rs13013209). -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 25, 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. -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 23, 2013	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Nemaline myopathy 2 Benign:4

Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 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, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 10, 2021	- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Apr 24, 2017

Variant summary: The NEB c.7839G>C (p.Lys2613Asn) variant involves the alteration of a conserved nucleotide and 2/3 in silico tools (SNPs&GO and Mutation Taster not captured here due to low reliability index and p-value, respectively) predict a damaging outcome. This variant was found in 50096/120722 control chromosomes (11150 homozygotes) from ExAC at a frequency of 0.4149699, which is approximately 117 times the estimated maximal expected allele frequency of a pathogenic NEB variant (0.0035355), thus this variant is a common benign polymorphism. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as benign/likely benign. Therefore, the variant of interest has been classified as Benign. -

Arthrogryposis multiplex congenita 6 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 10, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.87
BayesDel_addAF	Benign	-0.54	T
BayesDel_noAF	Benign	-0.41
CADD	Benign	22
DANN	Uncertain	1.0
Eigen	Pathogenic	0.86
Eigen_PC	Pathogenic	0.82
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.94	D;D;D;D;D;.;.
MetaRNN	Benign	0.0031	T;T;T;T;T;T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Pathogenic	3.5	M;M;.;M;M;M;M
MutationTaster	Benign	0.000059	P;P;P;P
PrimateAI	Uncertain	0.68	T
PROVEAN	Uncertain	-2.5	N;N;.;N;N;.;.
REVEL	Uncertain	0.30
Sift	Uncertain	0.026	D;D;.;T;D;.;.
Sift4G	Pathogenic	0.0	D;D;D;D;D;D;D
Polyphen		1.0	.;.;.;.;D;.;.
Vest4		0.80
MutPred		0.55		Loss of ubiquitination at K2613 (P = 0.027);Loss of ubiquitination at K2613 (P = 0.027);Loss of ubiquitination at K2613 (P = 0.027);Loss of ubiquitination at K2613 (P = 0.027);Loss of ubiquitination at K2613 (P = 0.027);Loss of ubiquitination at K2613 (P = 0.027);Loss of ubiquitination at K2613 (P = 0.027);
MPC		0.37
ClinPred		0.085	T
GERP RS		5.8
Varity_R		0.46
gMVP		0.55

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: rs13013209; hg19: chr2-152500449; COSMIC: COSV50813503;