2-151642629-C-T

Position:

chr2-151642629-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001164507.2(NEB):c.8318G>A(p.Arg2773Gln) variant causes a missense change. The variant allele was found at a frequency of 0.0257 in 1,613,648 control chromosomes in the GnomAD database, including 644 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. R2773W) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.019 ( 51 hom., cov: 33)

Exomes 𝑓: 0.026 ( 593 hom. )

Consequence

NEB
NM_001164507.2 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:11

Conservation

PhyloP100: 4.95

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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0036732256).

BP6

Variant 2-151642629-C-T is Benign according to our data. Variant chr2-151642629-C-T is described in ClinVar as [Benign]. Clinvar id is 129758.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-151642629-C-T is described in Lovd as [Benign]. Variant chr2-151642629-C-T is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.0188 (2869/152280) while in subpopulation SAS AF= 0.0453 (219/4830). AF 95% confidence interval is 0.0404. There are 51 homozygotes in gnomad4. There are 1393 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 51 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NEB	NM_001164507.2 linkuse as main transcript	c.8318G>A	p.Arg2773Gln	missense_variant	60/182	ENST00000427231.7
NEB	NM_001164508.2 linkuse as main transcript	c.8318G>A	p.Arg2773Gln	missense_variant	60/182	ENST00000397345.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NEB	ENST00000397345.8 linkuse as main transcript	c.8318G>A	p.Arg2773Gln	missense_variant	60/182	5	NM_001164508.2	P5	P20929-2
NEB	ENST00000427231.7 linkuse as main transcript	c.8318G>A	p.Arg2773Gln	missense_variant	60/182	5	NM_001164507.2	A2	P20929-3
NEB	ENST00000409198.5 linkuse as main transcript	c.8318G>A	p.Arg2773Gln	missense_variant	60/150	5			P20929-4

Frequencies

GnomAD3 genomes

AF:

0.0188

AC:

2865

AN:

152162

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00500

Gnomad AMI

AF:

0.0241

Gnomad AMR

AF:

0.0143

Gnomad ASJ

AF:

0.0458

Gnomad EAS

AF:

0.0110

Gnomad SAS

AF:

0.0445

Gnomad FIN

AF:

0.0150

Gnomad MID

AF:

0.0285

Gnomad NFE

AF:

0.0261

Gnomad OTH

AF:

0.0215

GnomAD3 exomes

AF:

0.0236

AC:

5875

AN:

248938

Hom.:

AF XY:

0.0252

AC XY:

3400

AN XY:

135044

show subpopulations

Gnomad AFR exome

AF:

0.00497

Gnomad AMR exome

AF:

0.00791

Gnomad ASJ exome

AF:

0.0494

Gnomad EAS exome

AF:

0.0135

Gnomad SAS exome

AF:

0.0463

Gnomad FIN exome

AF:

0.0158

Gnomad NFE exome

AF:

0.0257

Gnomad OTH exome

AF:

0.0215

GnomAD4 exome

AF:

0.0264

AC:

38538

AN:

1461368

Hom.:

593

Cov.:

AF XY:

0.0271

AC XY:

19710

AN XY:

726954

show subpopulations

Gnomad4 AFR exome

AF:

0.00412

Gnomad4 AMR exome

AF:

0.00863

Gnomad4 ASJ exome

AF:

0.0499

Gnomad4 EAS exome

AF:

0.00771

Gnomad4 SAS exome

AF:

0.0478

Gnomad4 FIN exome

AF:

0.0155

Gnomad4 NFE exome

AF:

0.0267

Gnomad4 OTH exome

AF:

0.0277

GnomAD4 genome

AF:

0.0188

AC:

2869

AN:

152280

Hom.:

Cov.:

AF XY:

0.0187

AC XY:

1393

AN XY:

74468

show subpopulations

Gnomad4 AFR

AF:

0.00498

Gnomad4 AMR

AF:

0.0143

Gnomad4 ASJ

AF:

0.0458

Gnomad4 EAS

AF:

0.0108

Gnomad4 SAS

AF:

0.0453

Gnomad4 FIN

AF:

0.0150

Gnomad4 NFE

AF:

0.0261

Gnomad4 OTH

AF:

0.0213

Alfa

AF:

0.0254

Hom.:

Bravo

AF:

0.0170

TwinsUK

AF:

0.0278

AC:

103

ALSPAC

AF:

0.0265

AC:

102

ESP6500AA

AF:

0.00558

AC:

ESP6500EA

AF:

0.0285

AC:

234

ExAC

AF:

0.0235

AC:

2837

Asia WGS

AF:

0.0380

AC:

132

AN:

3478

EpiCase

AF:

0.0257

EpiControl

AF:

0.0278

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:7

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, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jan 13, 2015	p.Arg2773Gln in exon 60 of NEB: This variant is not expected to have clinical si gnificance because it has been identified in 2.8% (234/8218) of European America n chromosomes from a broad population by the NHLBI Exome Sequencing Project (htt p://evs.gs.washington.edu/EVS; dbSNP rs35974308). -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 12, 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	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Oct 19, 2020	- -

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	- -

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.8318G>A (p.Arg2773Gln) variant involves the alteration of a conserved nucleotide and 3/4 in silico tools (SNPs&GO not captured here due to low reliability index) predict a damaging outcome. This variant was found in 2834/120142 control chromosomes (37 homozygotes) from ExAC at a frequency of 0.0235888, which is approximately 7 times the estimated maximal expected allele frequency of a pathogenic NEB variant (0.0035355), strongly supporting that this variant is likely a benign polymorphism. The variant is more common in East Asian sub-population with allele frequency of 4.5% (751/16334 chromosomes). 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.20

BayesDel_addAF

Benign

-0.42

BayesDel_noAF

Benign

-0.35

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.038

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

Eigen

Pathogenic

0.71

Eigen_PC

Uncertain

0.62

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.94

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

MetaRNN

Benign

0.0037

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

MetaSVM

Benign

-1.1

MutationAssessor

Pathogenic

3.7

H;H;.;H;H;H;H

MutationTaster

Benign

1.0

D;D;D;D

PrimateAI

Benign

0.46

PROVEAN

Benign

-1.3

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

REVEL

Benign

0.27

Sift

Benign

0.14

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

Sift4G

Uncertain

0.0070

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

Polyphen

1.0

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

Vest4

0.70

MPC

0.36

ClinPred

0.099

GERP RS

6.2

Varity_R

0.22

gMVP

0.28

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