rs201976154

Positions:

chr2-151519018-T-C

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 2P and 3B. PM2BP4_ModerateBP6

The NM_001164508.2(NEB):c.22642A>G(p.Lys7548Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000156 in 1,613,654 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00011 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00016 ( 0 hom. )

Consequence

NEB
NM_001164508.2 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4B:1

Conservation

PhyloP100: 1.75

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:

NEB (HGNC:):

NEB links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.10933238).

BP6

Variant 2-151519018-T-C is Benign according to our data. Variant chr2-151519018-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 465567.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=2}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NEB	NM_001164507.2 linkuse as main transcript	c.22642A>G	p.Lys7548Glu	missense_variant	155/182	ENST00000427231.7	NP_001157979.2
NEB	NM_001164508.2 linkuse as main transcript	c.22642A>G	p.Lys7548Glu	missense_variant	155/182	ENST00000397345.8	NP_001157980.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NEB	ENST00000397345.8 linkuse as main transcript	c.22642A>G	p.Lys7548Glu	missense_variant	155/182	5	NM_001164508.2	ENSP00000380505.3		P20929-2
NEB	ENST00000427231.7 linkuse as main transcript	c.22642A>G	p.Lys7548Glu	missense_variant	155/182	5	NM_001164507.2	ENSP00000416578.2		P20929-3

Frequencies

GnomAD3 genomes

AF:

0.000112

AC:

AN:

152226

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

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:

0.000220

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000185

AC:

AN:

248974

Hom.:

AF XY:

0.000193

AC XY:

AN XY:

135054

show subpopulations

Gnomad AFR exome

AF:

0.0000646

Gnomad AMR exome

AF:

0.000203

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000131

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000301

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000160

AC:

234

AN:

1461428

Hom.:

Cov.:

AF XY:

0.000176

AC XY:

128

AN XY:

726992

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.000179

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000928

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000177

Gnomad4 OTH exome

AF:

0.000248

GnomAD4 genome

AF:

0.000112

AC:

AN:

152226

Hom.:

Cov.:

AF XY:

0.0000672

AC XY:

AN XY:

74376

show subpopulations

Gnomad4 AFR

AF:

0.0000483

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:

0.000220

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000252

Hom.:

Bravo

AF:

0.000121

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000122

AC:

ExAC

AF:

0.000207

AC:

EpiCase

AF:

0.000873

EpiControl

AF:

0.000711

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Nemaline myopathy 2

Uncertain:2Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 28, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -
Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	Nov 11, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 24, 2024	- -

NEB-related disorder

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 12, 2024

The NEB c.22747A>G variant is predicted to result in the amino acid substitution p.Lys7583Glu. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.028% of alleles in individuals of European (Non-Finnish) descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Mar 23, 2024

In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.18

BayesDel_addAF

Benign

-0.27

BayesDel_noAF

Benign

-0.33

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.028

.;.;T;.;T;T;.;.

Eigen

Benign

0.19

Eigen_PC

Uncertain

0.32

FATHMM_MKL

Uncertain

0.86

LIST_S2

Uncertain

0.92

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

M_CAP

Benign

0.020

MetaRNN

Benign

0.11

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

MetaSVM

Benign

-0.98

MutationAssessor

Benign

0.090

N;.;.;.;N;.;.;.

PrimateAI

Uncertain

0.63

PROVEAN

Benign

-1.1

N;N;.;N;N;N;.;.

REVEL

Benign

0.15

Sift

Benign

0.64

T;T;.;T;T;T;.;.

Sift4G

Benign

0.085

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

Polyphen

0.21

.;.;.;.;B;.;.;.

Vest4

0.43

MVP

0.43

MPC

0.29

ClinPred

0.050

GERP RS

6.0

Varity_R

0.12

gMVP

0.23

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