rs375164626

Positions:

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM5BP4BS2_Supporting

The NM_001164507.2(NEB):c.7309C>T(p.Arg2437Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000143 in 1,613,680 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R2437G) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00014 ( 2 hom. )

Consequence

NEB
NM_001164507.2 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:7B:1

Conservation

PhyloP100: 2.17

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.

PM5

Other missense variant is known to change same aminoacid residue: Variant chr2-151650297-C-T is described in Lovd as [Likely_pathogenic].

BP4

Computational evidence support a benign effect (MetaRNN=0.28897315).

BS2

High Homozygotes in GnomAdExome4 at 2 AR geneVariant has number of homozygotes lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NEB	NM_001164507.2 linkuse as main transcript	c.7309C>T	p.Arg2437Trp	missense_variant	54/182	ENST00000427231.7
NEB	NM_001164508.2 linkuse as main transcript	c.7309C>T	p.Arg2437Trp	missense_variant	54/182	ENST00000397345.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NEB	ENST00000397345.8 linkuse as main transcript	c.7309C>T	p.Arg2437Trp	missense_variant	54/182	5	NM_001164508.2	P5	P20929-2
NEB	ENST00000427231.7 linkuse as main transcript	c.7309C>T	p.Arg2437Trp	missense_variant	54/182	5	NM_001164507.2	A2	P20929-3
NEB	ENST00000409198.5 linkuse as main transcript	c.7309C>T	p.Arg2437Trp	missense_variant	54/150	5			P20929-4

Frequencies

GnomAD3 genomes

AF:

0.000132

AC:

AN:

152074

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000966

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.000577

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000943

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000191

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000165

AC:

AN:

248974

Hom.:

AF XY:

0.000178

AC XY:

AN XY:

135056

show subpopulations

Gnomad AFR exome

AF:

0.000129

Gnomad AMR exome

AF:

0.000174

Gnomad ASJ exome

AF:

0.000497

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000464

Gnomad NFE exome

AF:

0.000222

Gnomad OTH exome

AF:

0.000331

GnomAD4 exome

AF:

0.000144

AC:

210

AN:

1461606

Hom.:

Cov.:

AF XY:

0.000164

AC XY:

119

AN XY:

727092

show subpopulations

Gnomad4 AFR exome

AF:

0.0000597

Gnomad4 AMR exome

AF:

0.000157

Gnomad4 ASJ exome

AF:

0.000842

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000812

Gnomad4 FIN exome

AF:

0.0000187

Gnomad4 NFE exome

AF:

0.000137

Gnomad4 OTH exome

AF:

0.000265

GnomAD4 genome

AF:

0.000132

AC:

AN:

152074

Hom.:

Cov.:

AF XY:

0.000121

AC XY:

AN XY:

74286

show subpopulations

Gnomad4 AFR

AF:

0.0000966

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.000577

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.0000943

Gnomad4 NFE

AF:

0.000191

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000197

Hom.:

Bravo

AF:

0.000144

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000122

AC:

ExAC

AF:

0.0000911

AC:

EpiCase

AF:

0.000164

EpiControl

AF:

0.000178

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:7Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:4

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Aug 10, 2023	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 27105866, 25214167, 34426522) -
Uncertain significance, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jan 05, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2023	NEB: PM2, BP1, BP4 -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Feb 06, 2023	- -

Nemaline myopathy 2

Uncertain:2Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Apr 18, 2019	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 30, 2024	- -
Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -

Nemaline myopathy 2;C5543431:Arthrogryposis multiplex congenita 6

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Jan 21, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.18

BayesDel_addAF

Benign

-0.34

BayesDel_noAF

Benign

-0.44

CADD

Uncertain

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.095

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

Eigen

Uncertain

0.29

Eigen_PC

Uncertain

0.22

FATHMM_MKL

Uncertain

0.85

LIST_S2

Uncertain

0.94

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

M_CAP

Benign

0.069

MetaRNN

Benign

0.29

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

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.8

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

MutationTaster

Benign

0.54

N;N;N;N

PrimateAI

Uncertain

0.49

PROVEAN

Uncertain

-2.9

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

REVEL

Benign

0.13

Sift

Uncertain

0.0040

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

Sift4G

Pathogenic

0.0010

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

Polyphen

0.99

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

Vest4

0.51

MVP

0.46

MPC

0.34

ClinPred

0.44

GERP RS

0.62

Varity_R

0.18

gMVP

0.66

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