rs34577613

Positions:

• chr2-151671094-C-T

Variant summary

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

The NM_001164508.2(NEB):​c.4435G>A​(p.Val1479Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.146 in 1,613,714 control chromosomes in the GnomAD database, including 26,248 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict 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.

• Frequency:
  • Genomes: 𝑓 0.21 (4822 hom., cov: 32)
  • Exomes 𝑓: 0.14 (21426 hom.)
• Consequence: NEB NM_001164508.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: 0.308

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=2.0170212E-4).
• BP6: Variant 2-151671094-C-T is Benign according to our data. Variant chr2-151671094-C-T is described in ClinVar as [Benign]. Clinvar id is 129744.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-151671094-C-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.538 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NEB	NM_001164507.2	c.4435G>A	p.Val1479Ile	missense_variant	38/182	ENST00000427231.7	NP_001157979.2
NEB	NM_001164508.2	c.4435G>A	p.Val1479Ile	missense_variant	38/182	ENST00000397345.8	NP_001157980.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NEB	ENST00000397345.8	c.4435G>A	p.Val1479Ile	missense_variant	38/182	5	NM_001164508.2	ENSP00000380505	P5
NEB	ENST00000427231.7	c.4435G>A	p.Val1479Ile	missense_variant	38/182	5	NM_001164507.2	ENSP00000416578	A2
NEB	ENST00000409198.5	c.4435G>A	p.Val1479Ile	missense_variant	38/150	5		ENSP00000386259
NEB	ENST00000484968.1	n.287G>A		non_coding_transcript_exon_variant	1/3	4

Frequencies

GnomAD3 genomes AF: 0.208 AC: 31550 AN: 151988 Hom.: 4796 Cov.: 32

Gnomad AFR AF: 0.383

Gnomad AMI AF: 0.148

Gnomad AMR AF: 0.126

Gnomad ASJ AF: 0.155

Gnomad EAS AF: 0.555

Gnomad SAS AF: 0.286

Gnomad FIN AF: 0.119

Gnomad MID AF: 0.127

Gnomad NFE AF: 0.105

Gnomad OTH AF: 0.195

GnomAD3 exomes AF: 0.183 AC: 45602 AN: 249248 Hom.: 6396 AF XY: 0.183 AC XY: 24733 AN XY: 135214

Gnomad AFR exome AF: 0.391

Gnomad AMR exome AF: 0.104

Gnomad ASJ exome AF: 0.161

Gnomad EAS exome AF: 0.544

Gnomad SAS exome AF: 0.290

Gnomad FIN exome AF: 0.125

Gnomad NFE exome AF: 0.106

Gnomad OTH exome AF: 0.160

GnomAD4 exome AF: 0.139 AC: 203548 AN: 1461608 Hom.: 21426 Cov.: 35 AF XY: 0.143 AC XY: 103634 AN XY: 727090

Gnomad4 AFR exome AF: 0.403

Gnomad4 AMR exome AF: 0.108

Gnomad4 ASJ exome AF: 0.157

Gnomad4 EAS exome AF: 0.568

Gnomad4 SAS exome AF: 0.281

Gnomad4 FIN exome AF: 0.125

Gnomad4 NFE exome AF: 0.105

Gnomad4 OTH exome AF: 0.172

GnomAD4 genome AF: 0.208 AC: 31635 AN: 152106 Hom.: 4822 Cov.: 32 AF XY: 0.209 AC XY: 15574 AN XY: 74374

Gnomad4 AFR AF: 0.383

Gnomad4 AMR AF: 0.126

Gnomad4 ASJ AF: 0.155

Gnomad4 EAS AF: 0.555

Gnomad4 SAS AF: 0.286

Gnomad4 FIN AF: 0.119

Gnomad4 NFE AF: 0.105

Gnomad4 OTH AF: 0.205

Alfa AF: 0.141 Hom.: 3790

Bravo AF: 0.216

TwinsUK AF: 0.0965 AC: 358

ALSPAC AF: 0.104 AC: 401

ESP6500AA AF: 0.357 AC: 1503

ESP6500EA AF: 0.109 AC: 920

ExAC AF: 0.190 AC: 22958

Asia WGS AF: 0.458 AC: 1589 AN: 3478

EpiCase AF: 0.0990

EpiControl AF: 0.105

ClinVar

Significance: Benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 28, 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	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Nov 26, 2014	p.Val1479Ile in exon 38 of NEB: This variant is not expected to have clinical si gnificance because it has been identified in 36% (1503/4208) of African American chromosomes by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu /EVS/; dbSNP rs34577613). -
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. -

Nemaline myopathy 2 Benign:4

Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
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, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 10, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

not provided Benign:3

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.4435G>A (p.Val1479Ile) variant involves the alteration of a non-conserved nucleotide and 4/4 in silico tools (SNPs&GO not captured due to low reliability index) predict a benign outcome. This variant was found in 22922/120734 control chromosomes (including 3255 homozygotes) from ExAC at a frequency of 0.1898554, which is approximately 54 times the estimated maximal expected allele frequency of a pathogenic NEB variant (0.0035355), thus this variant is a commom benign polymorphism. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as "likely benign/benign." Therefore, the variant of interest has been classified as Benign. -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Mar 07, 2019	- -

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	Benign	0.057
BayesDel_addAF	Benign	-0.83	T
BayesDel_noAF	Benign	-0.82
CADD	Benign	19
DANN	Benign	0.47
DEOGEN2	Benign	0.0026	.;.;T;.;T;.;.
Eigen	Benign	-1.0
Eigen_PC	Benign	-0.78
FATHMM_MKL	Benign	0.039	N
LIST_S2	Benign	0.28	T;T;T;T;T;.;.
MetaRNN	Benign	0.00020	T;T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-1.8	N;N;.;N;N;N;N
MutationTaster	Benign	1.0	P;P;P;P
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	0.34	N;N;.;N;N;.;.
REVEL	Benign	0.070
Sift	Benign	0.60	T;T;.;T;T;.;.
Sift4G	Benign	1.0	T;T;T;T;T;T;T
Polyphen		0.0	.;.;.;.;B;.;.
Vest4		0.072
MPC		0.045
ClinPred		0.0024	T
GERP RS		4.3
Varity_R		0.031
gMVP		0.078

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: rs34577613; hg19: chr2-152527608; COSMIC: COSV50874383;