2-151496329-C-G

Variant names:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001164508.2(NEB):c.24433G>C(p.Ala8145Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.647 in 1,610,432 control chromosomes in the GnomAD database, including 339,213 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.64 ( 31482 hom., cov: 31)

Exomes 𝑓: 0.65 ( 307731 hom. )

Consequence

NEB
NM_001164508.2 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:13

Conservation

PhyloP100: 1.99

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:

RIF1 (HGNC:23207): (replication timing regulatory factor 1) This gene encodes a protein that shares homology with the yeast teleomere binding protein, Rap1 interacting factor 1. This protein localizes to aberrant telomeres may be involved in DNA repair. Alternate splicing results in multiple transcript variants. [provided by RefSeq, Apr 2010]

RIF1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=5.199028E-6).

BP6

Variant 2-151496329-C-G is Benign according to our data. Variant chr2-151496329-C-G is described in ClinVar as [Benign]. Clinvar id is 95120.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-151496329-C-G is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.752 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NEB	NM_001164507.2 link	c.24433G>C	p.Ala8145Pro	missense_variant	Exon 173 of 182	ENST00000427231.7	NP_001157979.2
NEB	NM_001164508.2 link	c.24433G>C	p.Ala8145Pro	missense_variant	Exon 173 of 182	ENST00000397345.8	NP_001157980.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NEB	ENST00000397345.8 link	c.24433G>C	p.Ala8145Pro	missense_variant	Exon 173 of 182	5	NM_001164508.2	ENSP00000380505.3		P20929-2
NEB	ENST00000427231.7 link	c.24433G>C	p.Ala8145Pro	missense_variant	Exon 173 of 182	5	NM_001164507.2	ENSP00000416578.2		P20929-3

Frequencies

GnomAD3 genomes

AF:

0.640

AC:

97174

AN:

151872

Hom.:

31435

Cov.:

show subpopulations

Gnomad AFR

AF:

0.591

Gnomad AMI

AF:

0.508

Gnomad AMR

AF:

0.722

Gnomad ASJ

AF:

0.570

Gnomad EAS

AF:

0.773

Gnomad SAS

AF:

0.518

Gnomad FIN

AF:

0.685

Gnomad MID

AF:

0.699

Gnomad NFE

AF:

0.648

Gnomad OTH

AF:

0.645

GnomAD3 exomes

AF:

0.649

AC:

158963

AN:

245028

Hom.:

52402

AF XY:

0.638

AC XY:

84715

AN XY:

132756

show subpopulations

Gnomad AFR exome

AF:

0.592

Gnomad AMR exome

AF:

0.753

Gnomad ASJ exome

AF:

0.576

Gnomad EAS exome

AF:

0.772

Gnomad SAS exome

AF:

0.508

Gnomad FIN exome

AF:

0.675

Gnomad NFE exome

AF:

0.644

Gnomad OTH exome

AF:

0.658

GnomAD4 exome

AF:

0.647

AC:

943926

AN:

1458442

Hom.:

307731

Cov.:

AF XY:

0.642

AC XY:

465678

AN XY:

725246

show subpopulations

Gnomad4 AFR exome

AF:

0.599

Gnomad4 AMR exome

AF:

0.746

Gnomad4 ASJ exome

AF:

0.573

Gnomad4 EAS exome

AF:

0.795

Gnomad4 SAS exome

AF:

0.512

Gnomad4 FIN exome

AF:

0.677

Gnomad4 NFE exome

AF:

0.650

Gnomad4 OTH exome

AF:

0.647

GnomAD4 genome

AF:

0.640

AC:

97286

AN:

151990

Hom.:

31482

Cov.:

AF XY:

0.644

AC XY:

47794

AN XY:

74256

show subpopulations

Gnomad4 AFR

AF:

0.591

Gnomad4 AMR

AF:

0.722

Gnomad4 ASJ

AF:

0.570

Gnomad4 EAS

AF:

0.772

Gnomad4 SAS

AF:

0.519

Gnomad4 FIN

AF:

0.685

Gnomad4 NFE

AF:

0.648

Gnomad4 OTH

AF:

0.650

Alfa

AF:

0.645

Hom.:

10237

Bravo

AF:

0.645

TwinsUK

AF:

0.654

AC:

2425

ALSPAC

AF:

0.634

AC:

2443

ESP6500AA

AF:

0.595

AC:

2203

ESP6500EA

AF:

0.644

AC:

5281

ExAC

AF:

0.639

AC:

77175

Asia WGS

AF:

0.637

AC:

2216

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:13

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 14, 2013

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -

Nov 26, 2014

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This is a RefSeq error. The reference base (c.24538G) is the minor allele. This allele (G) has been identified in 36% (2917/8198) of European American chromosom es and 40% (1501/3704) of African American chromosomes by the NHLBI Exome Sequen cing Project (http://evs.gs.washington.edu/EVS/; dbSNP rs7575451) and thus meets criteria to be classified as benign. -

Jan 05, 2016

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Nemaline myopathy 2

Benign:4

Jul 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 16, 2020

Natera, Inc.

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided

Benign:3

Feb 27, 2017

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: The NEB c.24538G>C (p.Ala8180Pro) variant involves the alteration of a conserved nucleotide, which 3/4 in silico tools (query not functioning for SNPs&Go) predict a "benign" outcome. The variant of interest was observed in the large, broad control population, ExAC, with an allele frequency of 0.6499357 (74779/115056 (24235 homozygotes)). Therefore, suggesting that the C allele is the major allele observed in the general population. In addition, multiple clinical diagnostic laboratories classify the variant as Benign. Therefore, the variant of interest has been classified as Benign. -

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Feb 28, 2019

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Arthrogryposis multiplex congenita 6

Benign:1

Jul 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.048

BayesDel_addAF

Benign

-0.54

BayesDel_noAF

Benign

-0.40

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.0078

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

Eigen

Benign

-0.38

Eigen_PC

Benign

-0.28

FATHMM_MKL

Benign

0.22

LIST_S2

Benign

0.010

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

MetaRNN

Benign

0.0000052

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

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-1.4

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

PrimateAI

Uncertain

0.63

PROVEAN

Benign

2.4

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

REVEL

Uncertain

0.46

Sift

Benign

0.94

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

Sift4G

Benign

1.0

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

Polyphen

0.0

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

Vest4

0.15

MPC

0.31

ClinPred

0.017

GERP RS

4.1

Varity_R

0.051

gMVP

0.22

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