2-151650297-C-T

Position:

chr2-151650297-C-T

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM5BP4_StrongBP6_Very_StrongBA1

The NM_001164508.2(NEB):c.7310G>A(p.Arg2437Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0104 in 1,613,802 control chromosomes in the GnomAD database, including 1,528 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R2437W) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.022 ( 280 hom., cov: 32)

Exomes 𝑓: 0.0092 ( 1248 hom. )

Consequence

NEB
NM_001164508.2 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12

Conservation

PhyloP100: 0.883

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 -18 ACMG points.

PM5

Other missense variant is known to change same aminoacid residue: Variant chr2-151650298-G-A is described in Lovd as [Likely_pathogenic].

BP4

Computational evidence support a benign effect (MetaRNN=0.0013978481).

BP6

Variant 2-151650297-C-T is Benign according to our data. Variant chr2-151650297-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 95134.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-151650297-C-T is described in Lovd as [Likely_benign]. Variant chr2-151650297-C-T is described in Lovd as [Likely_pathogenic].

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.169 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NEB	NM_001164507.2 linkuse as main transcript	c.7310G>A	p.Arg2437Gln	missense_variant	54/182	ENST00000427231.7	NP_001157979.2
NEB	NM_001164508.2 linkuse as main transcript	c.7310G>A	p.Arg2437Gln	missense_variant	54/182	ENST00000397345.8	NP_001157980.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NEB	ENST00000397345.8 linkuse as main transcript	c.7310G>A	p.Arg2437Gln	missense_variant	54/182	5	NM_001164508.2	ENSP00000380505	P5	P20929-2
NEB	ENST00000427231.7 linkuse as main transcript	c.7310G>A	p.Arg2437Gln	missense_variant	54/182	5	NM_001164507.2	ENSP00000416578	A2	P20929-3
NEB	ENST00000409198.5 linkuse as main transcript	c.7310G>A	p.Arg2437Gln	missense_variant	54/150	5		ENSP00000386259		P20929-4

Frequencies

GnomAD3 genomes

AF:

0.0216

AC:

3285

AN:

152076

Hom.:

275

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00401

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.174

Gnomad ASJ

AF:

0.00490

Gnomad EAS

AF:

0.0562

Gnomad SAS

AF:

0.00166

Gnomad FIN

AF:

0.00236

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000897

Gnomad OTH

AF:

0.0315

GnomAD3 exomes

AF:

0.0371

AC:

9247

AN:

248964

Hom.:

990

AF XY:

0.0289

AC XY:

3901

AN XY:

135054

show subpopulations

Gnomad AFR exome

AF:

0.00355

Gnomad AMR exome

AF:

0.225

Gnomad ASJ exome

AF:

0.00398

Gnomad EAS exome

AF:

0.0561

Gnomad SAS exome

AF:

0.00137

Gnomad FIN exome

AF:

0.00311

Gnomad NFE exome

AF:

0.000780

Gnomad OTH exome

AF:

0.0313

GnomAD4 exome

AF:

0.00920

AC:

13445

AN:

1461608

Hom.:

1248

Cov.:

AF XY:

0.00796

AC XY:

5791

AN XY:

727098

show subpopulations

Gnomad4 AFR exome

AF:

0.00272

Gnomad4 AMR exome

AF:

0.216

Gnomad4 ASJ exome

AF:

0.00436

Gnomad4 EAS exome

AF:

0.0550

Gnomad4 SAS exome

AF:

0.00133

Gnomad4 FIN exome

AF:

0.00354

Gnomad4 NFE exome

AF:

0.000357

Gnomad4 OTH exome

AF:

0.0117

GnomAD4 genome

AF:

0.0217

AC:

3298

AN:

152194

Hom.:

280

Cov.:

AF XY:

0.0246

AC XY:

1833

AN XY:

74404

show subpopulations

Gnomad4 AFR

AF:

0.00400

Gnomad4 AMR

AF:

0.175

Gnomad4 ASJ

AF:

0.00490

Gnomad4 EAS

AF:

0.0555

Gnomad4 SAS

AF:

0.00166

Gnomad4 FIN

AF:

0.00236

Gnomad4 NFE

AF:

0.000897

Gnomad4 OTH

AF:

0.0312

Alfa

AF:

0.00454

Hom.:

Bravo

AF:

0.0352

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.00346

AC:

ESP6500EA

AF:

0.00170

AC:

ExAC

AF:

0.0278

AC:

3361

Asia WGS

AF:

0.0240

AC:

AN:

3478

EpiCase

AF:

0.000709

EpiControl

AF:

0.000415

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:6

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jan 13, 2015	p.Arg2437Gln in exon 54 of NEB: This variant is not expected to have clinical si gnificance because it has been identified in 18.3% (22/120) of Colombian chromos omes from a broad population by the 1000 Genomes Project (http://www.ncbi.nlm.ni h.gov/projects/SNP; dbSNP rs61730780). -
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	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 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. -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 30, 2013	- -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Nov 05, 2021	- -

not provided

Benign:3

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

Nemaline myopathy 2

Benign:3

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	- -
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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.67

BayesDel_noAF

Benign

-0.59

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.030

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

Eigen

Benign

0.10

Eigen_PC

Benign

0.20

FATHMM_MKL

Benign

0.45

LIST_S2

Uncertain

0.92

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

MetaRNN

Benign

0.0014

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

MetaSVM

Benign

-0.82

MutationAssessor

Benign

1.8

L;L;.;L;L;L;L

MutationTaster

Benign

0.94

N;N;N;N

PrimateAI

Benign

0.37

PROVEAN

Benign

-1.0

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

REVEL

Benign

0.068

Sift

Benign

0.057

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

Sift4G

Uncertain

0.012

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

Polyphen

0.50

.;.;.;.;P;.;.

Vest4

0.34

MPC

0.19

ClinPred

0.037

GERP RS

4.4

Varity_R

0.083

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