rs192402741

Positions:

chr2-151525997-G-C

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_001164508.2(NEB):c.22122C>G(p.Asp7374Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0044 in 1,613,972 control chromosomes in the GnomAD database, including 26 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 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 0.0032 ( 3 hom., cov: 32)

Exomes 𝑓: 0.0045 ( 23 hom. )

Consequence

NEB
NM_001164508.2 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:8

Conservation

PhyloP100: 0.392

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 Benign. Variant got -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.008312732).

BP6

Variant 2-151525997-G-C is Benign according to our data. Variant chr2-151525997-G-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 378269.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=5, Uncertain_significance=1}. Variant chr2-151525997-G-C is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0032 (488/152322) while in subpopulation NFE AF= 0.00587 (399/68030). AF 95% confidence interval is 0.00539. There are 3 homozygotes in gnomad4. There are 215 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NEB	NM_001164507.2 linkuse as main transcript	c.22122C>G	p.Asp7374Glu	missense_variant	150/182	ENST00000427231.7	NP_001157979.2
NEB	NM_001164508.2 linkuse as main transcript	c.22122C>G	p.Asp7374Glu	missense_variant	150/182	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.22122C>G	p.Asp7374Glu	missense_variant	150/182	5	NM_001164508.2	ENSP00000380505.3		P20929-2
NEB	ENST00000427231.7 linkuse as main transcript	c.22122C>G	p.Asp7374Glu	missense_variant	150/182	5	NM_001164507.2	ENSP00000416578.2		P20929-3

Frequencies

GnomAD3 genomes

AF:

0.00321

AC:

488

AN:

152204

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000820

Gnomad AMI

AF:

0.0132

Gnomad AMR

AF:

0.000917

Gnomad ASJ

AF:

0.00115

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.00132

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.00586

Gnomad OTH

AF:

0.00335

GnomAD3 exomes

AF:

0.00317

AC:

790

AN:

249106

Hom.:

AF XY:

0.00326

AC XY:

441

AN XY:

135122

show subpopulations

Gnomad AFR exome

AF:

0.000710

Gnomad AMR exome

AF:

0.000782

Gnomad ASJ exome

AF:

0.00179

Gnomad EAS exome

AF:

0.0000556

Gnomad SAS exome

AF:

0.000850

Gnomad FIN exome

AF:

0.00139

Gnomad NFE exome

AF:

0.00579

Gnomad OTH exome

AF:

0.00397

GnomAD4 exome

AF:

0.00453

AC:

6614

AN:

1461650

Hom.:

Cov.:

AF XY:

0.00454

AC XY:

3300

AN XY:

727114

show subpopulations

Gnomad4 AFR exome

AF:

0.000568

Gnomad4 AMR exome

AF:

0.000872

Gnomad4 ASJ exome

AF:

0.00187

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00101

Gnomad4 FIN exome

AF:

0.00155

Gnomad4 NFE exome

AF:

0.00550

Gnomad4 OTH exome

AF:

0.00340

GnomAD4 genome

AF:

0.00320

AC:

488

AN:

152322

Hom.:

Cov.:

AF XY:

0.00289

AC XY:

215

AN XY:

74486

show subpopulations

Gnomad4 AFR

AF:

0.000818

Gnomad4 AMR

AF:

0.000916

Gnomad4 ASJ

AF:

0.00115

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000414

Gnomad4 FIN

AF:

0.00132

Gnomad4 NFE

AF:

0.00587

Gnomad4 OTH

AF:

0.00331

Alfa

AF:

0.00541

Hom.:

Bravo

AF:

0.00292

TwinsUK

AF:

0.00485

AC:

ALSPAC

AF:

0.00493

AC:

ESP6500AA

AF:

0.000492

AC:

ESP6500EA

AF:

0.00512

AC:

ExAC

AF:

0.00340

AC:

411

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.00529

EpiControl

AF:

0.00516

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:8

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:4

Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 16, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2024	NEB: BS2 -

Nemaline myopathy 2

Uncertain:1Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 30, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

not specified

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 03, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Aug 24, 2015	- -

NEB-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 30, 2019

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.32

BayesDel_addAF

Benign

-0.47

BayesDel_noAF

Benign

-0.44

CADD

Benign

DANN

Benign

0.94

DEOGEN2

Benign

0.022

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

Eigen

Benign

-0.51

Eigen_PC

Benign

-0.44

FATHMM_MKL

Uncertain

0.91

LIST_S2

Benign

0.81

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

M_CAP

Benign

0.013

MetaRNN

Benign

0.0083

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

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.5

L;.;.;.;L;.;.;.

PrimateAI

Uncertain

0.55

PROVEAN

Benign

-1.1

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

REVEL

Benign

0.072

Sift

Benign

0.55

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

Sift4G

Benign

0.24

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

Polyphen

0.090

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

Vest4

0.49

MutPred

0.38

Gain of loop (P = 0.0502);.;.;.;Gain of loop (P = 0.0502);.;.;.;

MVP

0.34

MPC

0.085

ClinPred

0.0096

GERP RS

-0.81

Varity_R

0.084

gMVP

0.26

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