rs117636679

Positions:

chr2-151627640-C-G

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2BP4_StrongBS1_Supporting

The NM_001164507.2(NEB):c.10026G>C(p.Lys3342Asn) variant causes a missense change. The variant allele was found at a frequency of 0.000231 in 1,614,010 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.00021 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00023 ( 1 hom. )

Consequence

NEB
NM_001164507.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: 4.04

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 -3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.043038726).

BS1

Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00021 (32/152312) while in subpopulation EAS AF= 0.00348 (18/5178). AF 95% confidence interval is 0.00225. There are 0 homozygotes in gnomad4. There are 21 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NEB	NM_001164507.2 linkuse as main transcript	c.10026G>C	p.Lys3342Asn	missense_variant	69/182	ENST00000427231.7
NEB	NM_001164508.2 linkuse as main transcript	c.10026G>C	p.Lys3342Asn	missense_variant	69/182	ENST00000397345.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NEB	ENST00000397345.8 linkuse as main transcript	c.10026G>C	p.Lys3342Asn	missense_variant	69/182	5	NM_001164508.2	P5	P20929-2
NEB	ENST00000427231.7 linkuse as main transcript	c.10026G>C	p.Lys3342Asn	missense_variant	69/182	5	NM_001164507.2	A2	P20929-3
NEB	ENST00000409198.5 linkuse as main transcript	c.9297G>C	p.Lys3099Asn	missense_variant	66/150	5			P20929-4

Frequencies

GnomAD3 genomes

AF:

0.000210

AC:

AN:

152194

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000458

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00347

Gnomad SAS

AF:

0.000622

Gnomad FIN

AF:

0.0000941

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00143

GnomAD3 exomes

AF:

0.000229

AC:

AN:

249222

Hom.:

AF XY:

0.000215

AC XY:

AN XY:

135194

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000116

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00139

Gnomad SAS exome

AF:

0.000261

Gnomad FIN exome

AF:

0.000139

Gnomad NFE exome

AF:

0.000115

Gnomad OTH exome

AF:

0.000661

GnomAD4 exome

AF:

0.000233

AC:

341

AN:

1461698

Hom.:

Cov.:

AF XY:

0.000224

AC XY:

163

AN XY:

727134

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000179

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00587

Gnomad4 SAS exome

AF:

0.000267

Gnomad4 FIN exome

AF:

0.000281

Gnomad4 NFE exome

AF:

0.0000423

Gnomad4 OTH exome

AF:

0.000232

GnomAD4 genome

AF:

0.000210

AC:

AN:

152312

Hom.:

Cov.:

AF XY:

0.000282

AC XY:

AN XY:

74476

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000457

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00348

Gnomad4 SAS

AF:

0.000622

Gnomad4 FIN

AF:

0.0000941

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00142

Alfa

AF:

0.000112

Hom.:

Bravo

AF:

0.000238

ExAC

AF:

0.000314

AC:

Asia WGS

AF:

0.00173

AC:

AN:

3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Nemaline myopathy 2

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Aug 09, 2022	This sequence change replaces lysine, which is basic and polar, with asparagine, which is neutral and polar, at codon 3342 of the NEB protein (p.Lys3342Asn). This variant is present in population databases (rs117636679, gnomAD 0.1%). This variant has not been reported in the literature in individuals affected with NEB-related conditions. ClinVar contains an entry for this variant (Variation ID: 568797). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Not Available"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	Nov 11, 2019	- -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Revvity Omics, Revvity

Oct 16, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.90

BayesDel_addAF

Benign

-0.30

BayesDel_noAF

Benign

-0.24

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.26

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

Eigen

Pathogenic

0.86

Eigen_PC

Pathogenic

0.80

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.95

D;D;D;D;D;.;.

M_CAP

Benign

0.049

MetaRNN

Benign

0.043

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

MetaSVM

Uncertain

-0.24

MutationAssessor

Pathogenic

3.6

H;.;.;.;H;.;.

MutationTaster

Benign

1.0

D;D;D;D

PrimateAI

Uncertain

0.68

PROVEAN

Uncertain

-2.7

D;D;.;D;D;.;.

REVEL

Uncertain

0.32

Sift

Benign

0.047

D;D;.;D;D;.;.

Sift4G

Pathogenic

0.0

D;D;D;D;D;D;D

Polyphen

1.0

.;.;.;.;D;.;.

Vest4

0.61

MutPred

0.54

Loss of ubiquitination at K3099 (P = 0.0412);.;.;.;Loss of ubiquitination at K3099 (P = 0.0412);.;.;

MVP

0.68

MPC

0.37

ClinPred

0.45

GERP RS

5.6

Varity_R

0.58

gMVP

0.68

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