rs62167164

Positions:

chr2-151537930-G-C

Variant summary

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

The NM_001164508.2(NEB):c.21044C>G(p.Ser7015Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0106 in 1,613,300 control chromosomes in the GnomAD database, including 106 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0090 ( 11 hom., cov: 32)

Exomes 𝑓: 0.011 ( 95 hom. )

Consequence

NEB
NM_001164508.2 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: 9.60

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:

LOC124906081 (HGNC:):

LOC124906081 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=0.008066177).

BP6

Variant 2-151537930-G-C is Benign according to our data. Variant chr2-151537930-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 129724.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-151537930-G-C is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00902 (1374/152248) while in subpopulation NFE AF= 0.013 (886/68022). AF 95% confidence interval is 0.0123. There are 11 homozygotes in gnomad4. There are 704 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 11 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NEB	NM_001164507.2 linkuse as main transcript	c.21044C>G	p.Ser7015Cys	missense_variant	140/182	ENST00000427231.7	NP_001157979.2
NEB	NM_001164508.2 linkuse as main transcript	c.21044C>G	p.Ser7015Cys	missense_variant	140/182	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.21044C>G	p.Ser7015Cys	missense_variant	140/182	5	NM_001164508.2	ENSP00000380505.3		P20929-2
NEB	ENST00000427231.7 linkuse as main transcript	c.21044C>G	p.Ser7015Cys	missense_variant	140/182	5	NM_001164507.2	ENSP00000416578.2		P20929-3

Frequencies

GnomAD3 genomes

AF:

0.00903

AC:

1373

AN:

152130

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00183

Gnomad AMI

AF:

0.0132

Gnomad AMR

AF:

0.00373

Gnomad ASJ

AF:

0.00404

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00269

Gnomad FIN

AF:

0.0276

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.0130

Gnomad OTH

AF:

0.00956

GnomAD3 exomes

AF:

0.00892

AC:

2217

AN:

248626

Hom.:

AF XY:

0.00915

AC XY:

1234

AN XY:

134832

show subpopulations

Gnomad AFR exome

AF:

0.00162

Gnomad AMR exome

AF:

0.00223

Gnomad ASJ exome

AF:

0.00707

Gnomad EAS exome

AF:

0.0000558

Gnomad SAS exome

AF:

0.00390

Gnomad FIN exome

AF:

0.0234

Gnomad NFE exome

AF:

0.0121

Gnomad OTH exome

AF:

0.00977

GnomAD4 exome

AF:

0.0107

AC:

15671

AN:

1461052

Hom.:

Cov.:

AF XY:

0.0107

AC XY:

7792

AN XY:

726776

show subpopulations

Gnomad4 AFR exome

AF:

0.00120

Gnomad4 AMR exome

AF:

0.00226

Gnomad4 ASJ exome

AF:

0.00716

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00376

Gnomad4 FIN exome

AF:

0.0221

Gnomad4 NFE exome

AF:

0.0119

Gnomad4 OTH exome

AF:

0.00991

GnomAD4 genome

AF:

0.00902

AC:

1374

AN:

152248

Hom.:

Cov.:

AF XY:

0.00946

AC XY:

704

AN XY:

74426

show subpopulations

Gnomad4 AFR

AF:

0.00183

Gnomad4 AMR

AF:

0.00373

Gnomad4 ASJ

AF:

0.00404

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00290

Gnomad4 FIN

AF:

0.0276

Gnomad4 NFE

AF:

0.0130

Gnomad4 OTH

AF:

0.00946

Alfa

AF:

0.0113

Hom.:

Bravo

AF:

0.00677

TwinsUK

AF:

0.0121

AC:

ALSPAC

AF:

0.0122

AC:

ESP6500AA

AF:

0.00161

AC:

ESP6500EA

AF:

0.0118

AC:

ExAC

AF:

0.00899

AC:

1086

EpiCase

AF:

0.0119

EpiControl

AF:

0.0120

ClinVar

Significance: Benign/Likely 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	GeneDx	Apr 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	PreventionGenetics, part of Exact Sciences	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Oct 20, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jun 16, 2017	- -

Nemaline myopathy 2

Benign:4

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Likely 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Nov 11, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	May 18, 2021	- -

not provided

Benign:2

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2024	NEB: BP4, BS1, BS2 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.20

BayesDel_addAF

Benign

-0.24

BayesDel_noAF

Benign

-0.10

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Benign

0.054

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

Eigen

Uncertain

0.59

Eigen_PC

Uncertain

0.64

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Benign

0.79

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

MetaRNN

Benign

0.0081

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

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.81

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

PrimateAI

Benign

0.46

PROVEAN

Uncertain

-2.5

D;N;.;N;D;N;.;.;N

REVEL

Benign

0.26

Sift

Benign

0.37

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

Sift4G

Pathogenic

0.0

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

Polyphen

1.0

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

Vest4

0.76

MVP

0.55

MPC

0.34

ClinPred

0.029

GERP RS

5.6

Varity_R

0.34

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