rs141155976

Positions:

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_StrongBP6BS1BS2_Supporting

The NM_001164508.2(NEB):c.7126G>C(p.Val2376Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00145 in 1,613,870 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0015 ( 2 hom. )

Consequence

NEB
NM_001164508.2 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4B:6

Conservation

PhyloP100: 7.71

Variant links:

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]

NEB links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -10 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.01263243).

BP6

Variant 2-151650675-C-G is Benign according to our data. Variant chr2-151650675-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 257829.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=5, Uncertain_significance=4}. Variant chr2-151650675-C-G is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.00147 (2148/1461578) while in subpopulation MID AF= 0.00486 (28/5766). AF 95% confidence interval is 0.00345. There are 2 homozygotes in gnomad4_exome. There are 1076 alleles in male gnomad4_exome subpopulation. Median coverage is 31. This position pass quality control queck.

BS2

High Homozygotes in GnomAdExome4 at 2 AR geneVariant has number of homozygotes lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NEB	NM_001164507.2 linkuse as main transcript	c.7126G>C	p.Val2376Leu	missense_variant	53/182	ENST00000427231.7	NP_001157979.2
NEB	NM_001164508.2 linkuse as main transcript	c.7126G>C	p.Val2376Leu	missense_variant	53/182	ENST00000397345.8	NP_001157980.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
NEB	ENST00000397345.8 linkuse as main transcript	c.7126G>C	p.Val2376Leu	missense_variant	53/182	5	NM_001164508.2	ENSP00000380505.3	P20929-2
NEB	ENST00000427231.7 linkuse as main transcript	c.7126G>C	p.Val2376Leu	missense_variant	53/182	5	NM_001164507.2	ENSP00000416578.2	P20929-3
NEB	ENST00000409198.5 linkuse as main transcript	c.7126G>C	p.Val2376Leu	missense_variant	53/150	5		ENSP00000386259.1	P20929-4

Frequencies

GnomAD3 genomes

AF:

0.00126

AC:

192

AN:

152174

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000217

Gnomad AMI

AF:

0.00219

Gnomad AMR

AF:

0.000458

Gnomad ASJ

AF:

0.00663

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.000471

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00204

Gnomad OTH

AF:

0.00239

GnomAD3 exomes

AF:

0.00142

AC:

354

AN:

248650

Hom.:

AF XY:

0.00135

AC XY:

182

AN XY:

134872

show subpopulations

Gnomad AFR exome

AF:

0.000258

Gnomad AMR exome

AF:

0.000522

Gnomad ASJ exome

AF:

0.00577

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000523

Gnomad FIN exome

AF:

0.000744

Gnomad NFE exome

AF:

0.00205

Gnomad OTH exome

AF:

0.00182

GnomAD4 exome

AF:

0.00147

AC:

2148

AN:

1461578

Hom.:

Cov.:

AF XY:

0.00148

AC XY:

1076

AN XY:

727072

show subpopulations

Gnomad4 AFR exome

AF:

0.000269

Gnomad4 AMR exome

AF:

0.000559

Gnomad4 ASJ exome

AF:

0.00490

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000615

Gnomad4 FIN exome

AF:

0.000618

Gnomad4 NFE exome

AF:

0.00159

Gnomad4 OTH exome

AF:

0.00166

GnomAD4 genome

AF:

0.00126

AC:

192

AN:

152292

Hom.:

Cov.:

AF XY:

0.00125

AC XY:

AN XY:

74464

show subpopulations

Gnomad4 AFR

AF:

0.000217

Gnomad4 AMR

AF:

0.000458

Gnomad4 ASJ

AF:

0.00663

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000415

Gnomad4 FIN

AF:

0.000471

Gnomad4 NFE

AF:

0.00204

Gnomad4 OTH

AF:

0.00237

Alfa

AF:

0.00215

Hom.:

Bravo

AF:

0.00122

TwinsUK

AF:

0.000809

AC:

ALSPAC

AF:

0.00182

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.00274

AC:

ExAC

AF:

0.00144

AC:

174

Asia WGS

AF:

0.000866

AC:

AN:

3478

EpiCase

AF:

0.00235

EpiControl

AF:

0.00190

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4Benign:6

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:2Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 06, 2020	This variant is associated with the following publications: (PMID: 25203624) -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 16, 2015	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Jul 28, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2024	NEB: BP4 -

Nemaline myopathy 2

Uncertain:1Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 30, 2024	- -
Uncertain significance, 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -
Likely benign, no assertion criteria provided	clinical testing	Natera, Inc.	Nov 11, 2019	- -

not specified

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Sep 28, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 26, 2021

The c.7126G>C (p.V2376L) alteration is located in exon 53 (coding exon 51) of the NEB gene. This alteration results from a G to C substitution at nucleotide position 7126, causing the valine (V) at amino acid position 2376 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.46

BayesDel_addAF

Benign

-0.36

BayesDel_noAF

Benign

-0.30

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.12

.;.;T;.;T;.;.

Eigen

Uncertain

0.63

Eigen_PC

Uncertain

0.57

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.77

T;D;D;T;T;.;.

M_CAP

Benign

0.025

MetaRNN

Benign

0.013

T;T;T;T;T;T;T

MetaSVM

Benign

-0.76

MutationAssessor

Uncertain

2.8

M;M;.;M;M;M;M

PrimateAI

Uncertain

0.49

PROVEAN

Benign

-1.4

N;N;.;N;N;.;.

REVEL

Benign

0.17

Sift

Benign

0.035

D;T;.;T;D;.;.

Sift4G

Pathogenic

0.0

D;D;D;D;D;D;D

Polyphen

1.0

.;.;.;.;D;.;.

Vest4

0.56

MVP

0.46

MPC

0.34

ClinPred

0.039

GERP RS

5.4

Varity_R

0.29

gMVP

0.46

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over