rs45612241

Positions:

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_StrongBP6_Very_Strong

The NM_001164508.2(NEB):c.15821A>T(p.Asn5274Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 11/16 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.014 ( 10 hom., cov: 5)

Exomes 𝑓: 0.023 ( 1228 hom. )

Failed GnomAD Quality Control

Consequence

NEB
NM_001164508.2 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 1.08

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 Benign. Variant got -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.002429992).

BP6

Variant 2-151583609-T-A is Benign according to our data. Variant chr2-151583609-T-A is described in ClinVar as [Likely_benign]. Clinvar id is 257755.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-151583609-T-A is described in Lovd as [Benign]. Variant chr2-151583609-T-A is described in Lovd as [Likely_benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NEB	NM_001164507.2 linkuse as main transcript	c.15821A>T	p.Asn5274Ile	missense_variant	101/182	ENST00000427231.7	NP_001157979.2
NEB	NM_001164508.2 linkuse as main transcript	c.15821A>T	p.Asn5274Ile	missense_variant	101/182	ENST00000397345.8	NP_001157980.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
NEB	ENST00000397345.8 linkuse as main transcript	c.15821A>T	p.Asn5274Ile	missense_variant	101/182	5	NM_001164508.2	ENSP00000380505.3	P20929-2
NEB	ENST00000427231.7 linkuse as main transcript	c.15821A>T	p.Asn5274Ile	missense_variant	101/182	5	NM_001164507.2	ENSP00000416578.2	P20929-3
NEB	ENST00000413693.5 linkuse as main transcript	c.11A>T	p.Asn4Ile	missense_variant	1/74	5		ENSP00000410961.1	H0Y786
NEB	ENST00000409198.5 linkuse as main transcript	c.11602-7255A>T		intron_variant		5		ENSP00000386259.1	P20929-4

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

311

AN:

22738

Hom.:

Cov.:

FAILED QC

Gnomad AFR

AF:

0.00481

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0115

Gnomad ASJ

AF:

0.00649

Gnomad EAS

AF:

0.00163

Gnomad SAS

AF:

0.0101

Gnomad FIN

AF:

0.0203

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0221

Gnomad OTH

AF:

0.00606

GnomAD3 exomes

AF:

0.0183

AC:

803

AN:

43820

Hom.:

154

AF XY:

0.0187

AC XY:

415

AN XY:

22220

show subpopulations

Gnomad AFR exome

AF:

0.00420

Gnomad AMR exome

AF:

0.0111

Gnomad ASJ exome

AF:

0.00683

Gnomad EAS exome

AF:

0.000457

Gnomad SAS exome

AF:

0.0107

Gnomad FIN exome

AF:

0.0291

Gnomad NFE exome

AF:

0.0324

Gnomad OTH exome

AF:

0.0186

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0233

AC:

8815

AN:

378320

Hom.:

1228

Cov.:

AF XY:

0.0228

AC XY:

4532

AN XY:

198908

show subpopulations

Gnomad4 AFR exome

AF:

0.00345

Gnomad4 AMR exome

AF:

0.0106

Gnomad4 ASJ exome

AF:

0.00695

Gnomad4 EAS exome

AF:

0.000132

Gnomad4 SAS exome

AF:

0.0114

Gnomad4 FIN exome

AF:

0.0252

Gnomad4 NFE exome

AF:

0.0305

Gnomad4 OTH exome

AF:

0.0221

GnomAD4 genome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0137

AC:

311

AN:

22756

Hom.:

Cov.:

AF XY:

0.0124

AC XY:

123

AN XY:

9928

show subpopulations

Gnomad4 AFR

AF:

0.00478

Gnomad4 AMR

AF:

0.0115

Gnomad4 ASJ

AF:

0.00649

Gnomad4 EAS

AF:

0.00165

Gnomad4 SAS

AF:

0.0104

Gnomad4 FIN

AF:

0.0203

Gnomad4 NFE

AF:

0.0221

Gnomad4 OTH

AF:

0.00599

Alfa

AF:

0.00130

Hom.:

ExAC

AF:

0.00463

AC:

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 01, 2017	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

not provided

Benign:1

Likely benign, no assertion criteria provided

clinical testing

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.13

BayesDel_noAF

Benign

-0.43

CADD

Benign

DANN

Benign

0.97

DEOGEN2

Benign

0.021

.;T;.;T;.;.

Eigen

Benign

-0.098

Eigen_PC

Benign

-0.11

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.55

T;T;T;T;.;.

MetaRNN

Benign

0.0024

T;T;T;T;T;T

MetaSVM

Benign

-1.1

PROVEAN

Benign

-1.5

N;.;N;N;.;.

REVEL

Benign

0.054

Sift

Benign

0.064

T;.;D;T;.;.

Sift4G

Pathogenic

0.0010

D;D;D;D;D;D

Vest4

0.52

MPC

0.36

ClinPred

0.0084

GERP RS

3.8

gMVP

0.011

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