rs1227592399

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.

The NM_001164507.2(NEB):c.12370G>A(p.Gly4124Ser) variant causes a missense change involving the alteration of a conserved nucleotide. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. G4124G) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0 ( 0 hom., cov: 4)

Exomes 𝑓: 0.000056 ( 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: 7.50

Publications

0 publications found

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 Gene-Disease associations (from GenCC):

nemaline myopathy 2
Inheritance: AR, AD Classification: DEFINITIVE, STRONG, LIMITED Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), Myriad Women’s Health, G2P, Ambry Genetics
childhood-onset nemaline myopathy
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
intermediate nemaline myopathy
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
typical nemaline myopathy
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
lethal multiple pterygium syndrome
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
severe congenital nemaline myopathy
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

NEB links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NEB	NM_001164507.2 link	c.12370G>A	p.Gly4124Ser	missense_variant	Exon 82 of 182	ENST00000427231.7	NP_001157979.2
NEB	NM_001164508.2 link	c.12370G>A	p.Gly4124Ser	missense_variant	Exon 82 of 182	ENST00000397345.8	NP_001157980.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
NEB	ENST00000397345.8 link	c.12370G>A	p.Gly4124Ser	missense_variant	Exon 82 of 182	5	NM_001164508.2	ENSP00000380505.3	P20929-2
NEB	ENST00000427231.7 link	c.12370G>A	p.Gly4124Ser	missense_variant	Exon 82 of 182	5	NM_001164507.2	ENSP00000416578.2	P20929-3
NEB	ENST00000409198.5 link	c.11601+1172G>A		intron_variant	Intron 78 of 149	5		ENSP00000386259.1	P20929-4

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

AN:

22976

Hom.:

Cov.:

Gnomad AFR

AF:

0.00

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00

AC:

AN:

4482

AF XY:

0.00

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000565

AC:

AN:

70822

Hom.:

Cov.:

AF XY:

0.0000552

AC XY:

AN XY:

36234

show subpopulations

African (AFR)

AF:

0.000262

AC:

AN:

3824

American (AMR)

AF:

0.00

AC:

AN:

4012

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3058

East Asian (EAS)

AF:

0.00

AC:

AN:

6772

South Asian (SAS)

AF:

0.00

AC:

AN:

3126

European-Finnish (FIN)

AF:

0.00

AC:

AN:

2706

Middle Eastern (MID)

AF:

0.00

AC:

AN:

354

European-Non Finnish (NFE)

AF:

0.0000710

AC:

AN:

42270

Other (OTH)

AF:

0.00

AC:

AN:

4700

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.613

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

22976

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

9906

African (AFR)

AF:

0.00

AC:

AN:

7934

American (AMR)

AF:

0.00

AC:

AN:

1918

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

786

East Asian (EAS)

AF:

0.00

AC:

AN:

1130

South Asian (SAS)

AF:

0.00

AC:

AN:

878

European-Finnish (FIN)

AF:

0.00

AC:

AN:

350

Middle Eastern (MID)

AF:

0.00

AC:

AN:

110

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

9398

Other (OTH)

AF:

0.00

AC:

AN:

320

Alfa

AF:

0.00

Hom.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Nemaline myopathy 2

Uncertain:2

Mar 11, 2020

Natera, Inc.

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jun 13, 2017

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.079

BayesDel_noAF

Benign

-0.35

CADD

Uncertain

(source)

DANN

Benign

0.93

DEOGEN2

Benign

0.11

.;T;.;.;.

Eigen

Uncertain

0.51

Eigen_PC

Uncertain

0.47

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.97

D;D;D;.;.

M_CAP

Uncertain

0.093

MetaRNN

Uncertain

0.68

D;D;D;D;D

MetaSVM

Benign

-0.55

PhyloP100

7.5

PROVEAN

Benign

-1.9

N;.;N;.;.

REVEL

Benign

0.18

Sift

Uncertain

0.0090

D;.;D;.;.

Sift4G

Pathogenic

0.0

D;D;D;D;D

Vest4

0.72

MutPred

0.52

Gain of phosphorylation at G4124 (P = 0.0744);Gain of phosphorylation at G4124 (P = 0.0744);Gain of phosphorylation at G4124 (P = 0.0744);Gain of phosphorylation at G4124 (P = 0.0744);Gain of phosphorylation at G4124 (P = 0.0744);

MVP

0.57

MPC

0.34

ClinPred

0.64

GERP RS

4.1

gMVP

0.024

Mutation Taster

=53/47

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over