2-151665469-A-G

Position:

chr2-151665469-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001164508.2(NEB):c.5102T>C(p.Val1701Ala) variant causes a missense change. The variant allele was found at a frequency of 0.00313 in 1,611,368 control chromosomes in the GnomAD database, including 125 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0043 ( 15 hom., cov: 32)

Exomes 𝑓: 0.0030 ( 110 hom. )

Consequence

NEB
NM_001164508.2 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: 6.13

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=0.0027567446).

BP6

Variant 2-151665469-A-G is Benign according to our data. Variant chr2-151665469-A-G is described in ClinVar as [Benign]. Clinvar id is 129745.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-151665469-A-G is described in Lovd as [Likely_benign].

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0635 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.5102T>C	p.Val1701Ala	missense_variant	42/182	ENST00000427231.7	NP_001157979.2
NEB	NM_001164508.2 linkuse as main transcript	c.5102T>C	p.Val1701Ala	missense_variant	42/182	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.5102T>C	p.Val1701Ala	missense_variant	42/182	5	NM_001164508.2	ENSP00000380505.3	P20929-2
NEB	ENST00000427231.7 linkuse as main transcript	c.5102T>C	p.Val1701Ala	missense_variant	42/182	5	NM_001164507.2	ENSP00000416578.2	P20929-3
NEB	ENST00000409198.5 linkuse as main transcript	c.5102T>C	p.Val1701Ala	missense_variant	42/150	5		ENSP00000386259.1	P20929-4

Frequencies

GnomAD3 genomes

AF:

0.00427

AC:

644

AN:

150994

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000536

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00804

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.0698

Gnomad SAS

AF:

0.00319

Gnomad FIN

AF:

0.00810

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000517

Gnomad OTH

AF:

0.00240

GnomAD3 exomes

AF:

0.00880

AC:

2168

AN:

246388

Hom.:

AF XY:

0.00817

AC XY:

1091

AN XY:

133576

show subpopulations

Gnomad AFR exome

AF:

0.000328

Gnomad AMR exome

AF:

0.0135

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0770

Gnomad SAS exome

AF:

0.00236

Gnomad FIN exome

AF:

0.00688

Gnomad NFE exome

AF:

0.000698

Gnomad OTH exome

AF:

0.00568

GnomAD4 exome

AF:

0.00301

AC:

4393

AN:

1460256

Hom.:

110

Cov.:

AF XY:

0.00296

AC XY:

2151

AN XY:

726258

show subpopulations

Gnomad4 AFR exome

AF:

0.000179

Gnomad4 AMR exome

AF:

0.0127

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0654

Gnomad4 SAS exome

AF:

0.00210

Gnomad4 FIN exome

AF:

0.00794

Gnomad4 NFE exome

AF:

0.000263

Gnomad4 OTH exome

AF:

0.00552

GnomAD4 genome

AF:

0.00426

AC:

643

AN:

151112

Hom.:

Cov.:

AF XY:

0.00476

AC XY:

351

AN XY:

73814

show subpopulations

Gnomad4 AFR

AF:

0.000535

Gnomad4 AMR

AF:

0.00803

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.0694

Gnomad4 SAS

AF:

0.00319

Gnomad4 FIN

AF:

0.00810

Gnomad4 NFE

AF:

0.000517

Gnomad4 OTH

AF:

0.00332

Alfa

AF:

0.00381

Hom.:

Bravo

AF:

0.00467

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.000258

AC:

ESP6500EA

AF:

0.000484

AC:

ExAC

AF:

0.00804

AC:

971

Asia WGS

AF:

0.0250

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 13, 2015	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 18, 2016	- -
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	-	- -

not provided

Benign:3

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
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.5102T>C (p.Val1701Ala) variant involves the alteration of a conserved nucleotide and is predicted to be benign by 2/4 in silico tools (SNPs&GO not captured due to low reliability index). This variant was found in 962/107782 control chromosomes (24 homozygotes) from ExAC, predominantly observed in the East Asian subpopulation at a frequency of 0.081239 (640/7878). This frequency is about 23 times the estimated maximal expected allele frequency of a pathogenic NEB variant (0.0035355), suggesting this is likely a benign polymorphism found primarily in the populations of East Asian origin. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as benign. Taken together, this variant is classified as benign. -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Mar 26, 2018	- -

Nemaline myopathy 2

Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 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, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.18

BayesDel_addAF

Benign

-0.51

BayesDel_noAF

Benign

-0.45

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.034

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

Eigen

Uncertain

0.28

Eigen_PC

Uncertain

0.40

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.81

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

MetaRNN

Benign

0.0028

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

MetaSVM

Benign

-0.98

MutationAssessor

Benign

1.2

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

PrimateAI

Benign

0.48

PROVEAN

Benign

-1.9

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

REVEL

Benign

0.11

Sift

Benign

0.29

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

Sift4G

Pathogenic

0.0010

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

Polyphen

0.62

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

Vest4

0.51

MVP

0.32

MPC

0.27

ClinPred

0.038

GERP RS

4.8

Varity_R

0.19

gMVP

0.47

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