Variant rs1376744526 details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 0P and 0B.

The NM_001164507.2(NEB):c.12769C>T(p.Arg4257Cys) variant causes a missense change. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R4257H) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000049 ( 0 hom., cov: 8)

Exomes 𝑓: 0.000029 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

NEB
NM_001164507.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:2

Conservation

PhyloP100: 3.82

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 Uncertain_significance. Variant got 0 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NEB	NM_001164507.2 linkuse as main transcript	c.12769C>T	p.Arg4257Cys	missense_variant	85/182	ENST00000427231.7
NEB	NM_001164508.2 linkuse as main transcript	c.12769C>T	p.Arg4257Cys	missense_variant	85/182	ENST00000397345.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NEB	ENST00000397345.8 linkuse as main transcript	c.12769C>T	p.Arg4257Cys	missense_variant	85/182	5	NM_001164508.2	P5	P20929-2
NEB	ENST00000427231.7 linkuse as main transcript	c.12769C>T	p.Arg4257Cys	missense_variant	85/182	5	NM_001164507.2	A2	P20929-3
NEB	ENST00000409198.5 linkuse as main transcript	c.11601+4959C>T		intron_variant		5			P20929-4

Frequencies

GnomAD3 genomes

AF:

0.0000485

AC:

AN:

61820

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000799

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000580

Gnomad OTH

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0000294

AC:

AN:

441778

Hom.:

Cov.:

AF XY:

0.0000215

AC XY:

AN XY:

232596

show subpopulations

Gnomad4 AFR exome

AF:

0.0000984

Gnomad4 AMR exome

AF:

0.000170

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000455

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000241

Gnomad4 OTH exome

AF:

0.0000445

GnomAD4 genome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0000485

AC:

AN:

61820

Hom.:

Cov.:

AF XY:

0.0000693

AC XY:

AN XY:

28858

show subpopulations

Gnomad4 AFR

AF:

0.0000799

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000580

Gnomad4 OTH

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Nemaline myopathy 2

Uncertain:2

Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	Nov 11, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 02, 2017	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Uncertain

0.033

BayesDel_noAF

Benign

-0.19

CADD

Uncertain

DANN

Benign

0.73

DEOGEN2

Benign

0.036

.;T;.;.;.

Eigen

Benign

-0.075

Eigen_PC

Benign

-0.11

FATHMM_MKL

Uncertain

0.94

LIST_S2

Uncertain

0.96

D;D;D;.;.

M_CAP

Benign

0.056

MetaRNN

Uncertain

0.51

D;D;D;D;D

MetaSVM

Benign

-0.87

MutationTaster

Benign

1.0

D;D;D;D

PROVEAN

Benign

-2.0

N;.;N;.;.

REVEL

Benign

0.20

Sift

Uncertain

0.0070

D;.;D;.;.

Sift4G

Pathogenic

0.0

D;D;D;D;D

Vest4

0.53

MutPred

0.65

Loss of MoRF binding (P = 0.0126);Loss of MoRF binding (P = 0.0126);Loss of MoRF binding (P = 0.0126);Loss of MoRF binding (P = 0.0126);Loss of MoRF binding (P = 0.0126);

MVP

0.62

MPC

0.37

ClinPred

0.25

GERP RS

2.3

gMVP

0.0029

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