Variant rs1365594299 details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PP3_Moderate

The NM_001164507.2(NEB):c.12596C>T(p.Pro4199Leu) variant causes a missense change. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. P4199P) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000012 ( 0 hom., cov: 11)

Exomes 𝑓: 0.000013 ( 3 hom. )

Failed GnomAD Quality Control

Consequence

NEB
NM_001164507.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:2

Conservation

PhyloP100: 4.40

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 2 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.926

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NEB	NM_001164507.2 linkuse as main transcript	c.12596C>T	p.Pro4199Leu	missense_variant	83/182	ENST00000427231.7
NEB	NM_001164508.2 linkuse as main transcript	c.12596C>T	p.Pro4199Leu	missense_variant	83/182	ENST00000397345.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NEB	ENST00000397345.8 linkuse as main transcript	c.12596C>T	p.Pro4199Leu	missense_variant	83/182	5	NM_001164508.2	P5	P20929-2
NEB	ENST00000427231.7 linkuse as main transcript	c.12596C>T	p.Pro4199Leu	missense_variant	83/182	5	NM_001164507.2	A2	P20929-3
NEB	ENST00000409198.5 linkuse as main transcript	c.11601+2262C>T		intron_variant		5			P20929-4

Frequencies

GnomAD3 genomes

AF:

0.0000123

AC:

AN:

81406

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000298

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

GnomAD3 exomes

AF:

0.0000477

AC:

AN:

83828

Hom.:

AF XY:

0.00

AC XY:

AN XY:

45488

show subpopulations

Gnomad AFR exome

AF:

0.000273

Gnomad AMR exome

AF:

0.000200

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0000128

AC:

AN:

623588

Hom.:

Cov.:

AF XY:

0.00000624

AC XY:

AN XY:

320434

show subpopulations

Gnomad4 AFR exome

AF:

0.0000727

Gnomad4 AMR exome

AF:

0.000116

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000928

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000123

AC:

AN:

81406

Hom.:

Cov.:

AF XY:

0.0000261

AC XY:

AN XY:

38372

show subpopulations

Gnomad4 AFR

AF:

0.0000298

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:

0.00

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	Invitae	Dec 20, 2016	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.29

BayesDel_noAF

Benign

-0.35

CADD

Uncertain

DANN

Benign

0.63

Eigen

Uncertain

0.23

Eigen_PC

Benign

0.087

FATHMM_MKL

Uncertain

0.86

LIST_S2

Uncertain

0.88

D;D;D;.;.

M_CAP

Benign

0.058

MetaRNN

Pathogenic

0.93

D;D;D;D;D

MetaSVM

Uncertain

0.39

MutationTaster

Benign

0.99

D;D;D;D

PROVEAN

Benign

-1.6

N;.;N;.;.

REVEL

Uncertain

0.39

Sift

Uncertain

0.020

D;.;D;.;.

Sift4G

Pathogenic

0.0

D;D;D;D;D

Vest4

0.55

MutPred

0.83

Loss of disorder (P = 0.0446);Loss of disorder (P = 0.0446);Loss of disorder (P = 0.0446);Loss of disorder (P = 0.0446);Loss of disorder (P = 0.0446);

MVP

0.79

MPC

0.33

ClinPred

0.091

GERP RS

3.7

gMVP

0.0068

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