Variant rs62174690 details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 0P and 1B. BP4

The NM_001164507.2(NEB):c.16544A>T(p.Lys5515Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 11/17 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K5515T) has been classified as Benign.

Frequency

Genomes: 𝑓 0.0000081 ( 0 hom., cov: 17)

Exomes 𝑓: 7.4e-7 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

NEB
NM_001164507.2 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.29

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 Likely_benign. Variant got -1 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.26775432).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NEB	NM_001164507.2 linkuse as main transcript	c.16544A>T	p.Lys5515Met	missense_variant	105/182	ENST00000427231.7
NEB	NM_001164508.2 linkuse as main transcript	c.16544A>T	p.Lys5515Met	missense_variant	105/182	ENST00000397345.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NEB	ENST00000397345.8 linkuse as main transcript	c.16544A>T	p.Lys5515Met	missense_variant	105/182	5	NM_001164508.2	P5	P20929-2
NEB	ENST00000427231.7 linkuse as main transcript	c.16544A>T	p.Lys5515Met	missense_variant	105/182	5	NM_001164507.2	A2	P20929-3
NEB	ENST00000413693.5 linkuse as main transcript	c.734A>T	p.Lys245Met	missense_variant	5/74	5
NEB	ENST00000409198.5 linkuse as main transcript	c.11602-3144A>T		intron_variant		5			P20929-4

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

AN:

123990

Hom.:

Cov.:

FAILED QC

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:

0.000265

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

7.36e-7

AC:

AN:

1358928

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

671238

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

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:

9.59e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00000807

AC:

AN:

123990

Hom.:

Cov.:

AF XY:

0.0000170

AC XY:

AN XY:

58750

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000265

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.12

BayesDel_noAF

Benign

-0.41

Cadd

Benign

Dann

Benign

0.92

Eigen

Benign

-0.049

Eigen_PC

Benign

-0.063

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.85

T;T;D;D;.;.

M_CAP

Benign

0.059

MetaRNN

Benign

0.27

T;T;T;T;T;T

MetaSVM

Benign

-0.93

MutationTaster

Benign

0.84

D;D;D;D

PROVEAN

Benign

-0.93

N;.;N;D;.;.

REVEL

Benign

0.14

Sift

Uncertain

0.010

D;.;D;D;.;.

Sift4G

Uncertain

0.0090

D;D;D;D;D;D

Vest4

0.32

MutPred

0.58

Loss of methylation at K5515 (P = 0.0163);Loss of methylation at K5515 (P = 0.0163);Loss of methylation at K5515 (P = 0.0163);.;Loss of methylation at K5515 (P = 0.0163);Loss of methylation at K5515 (P = 0.0163);

MVP

0.45

MPC

0.35

ClinPred

0.69

GERP RS

3.6

gMVP

0.017

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

Computational scores

Splicing

Publications

LitVar

Other links and lift over