2-151516460-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001164507.2(NEB):c.22904G>A(p.Gly7635Glu) variant causes a missense change. The variant allele was found at a frequency of 0.00162 in 1,605,246 control chromosomes in the GnomAD database, including 37 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/23 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. G7635G) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0023 ( 8 hom., cov: 32)

Exomes 𝑓: 0.0016 ( 29 hom. )

Consequence

NEB
NM_001164507.2 missense

Scores

Splicing: ADA: 0.003922

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 5.02

Publications

8 publications found

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 was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.005690187).

BP6

Variant 2-151516460-C-T is Benign according to our data. Variant chr2-151516460-C-T is described in ClinVar as Benign. ClinVar VariationId is 194291.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.00226 (344/152204) while in subpopulation EAS AF = 0.0444 (230/5184). AF 95% confidence interval is 0.0397. There are 8 homozygotes in GnomAd4. There are 180 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 8 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NEB	NM_001164507.2 link	c.22904G>A	p.Gly7635Glu	missense_variant	Exon 157 of 182	ENST00000427231.7	NP_001157979.2
NEB	NM_001164508.2 link	c.22904G>A	p.Gly7635Glu	missense_variant	Exon 157 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.22904G>A	p.Gly7635Glu	missense_variant	Exon 157 of 182	5	NM_001164508.2	ENSP00000380505.3
NEB	ENST00000427231.7 link	c.22904G>A	p.Gly7635Glu	missense_variant	Exon 157 of 182	5	NM_001164507.2	ENSP00000416578.2

Frequencies

GnomAD3 genomes

AF:

0.00228

AC:

346

AN:

152086

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000507

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00380

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.0450

Gnomad SAS

AF:

0.00270

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000206

Gnomad OTH

AF:

0.00287

GnomAD2 exomes

AF:

0.00519

AC:

1283

AN:

247432

AF XY:

0.00477

show subpopulations

Gnomad AFR exome

AF:

0.000259

Gnomad AMR exome

AF:

0.00990

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0468

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000312

Gnomad OTH exome

AF:

0.00283

GnomAD4 exome

AF:

0.00155

AC:

2254

AN:

1453042

Hom.:

Cov.:

AF XY:

0.00147

AC XY:

1064

AN XY:

723208

show subpopulations

African (AFR)

AF:

0.000330

AC:

AN:

33302

American (AMR)

AF:

0.00918

AC:

409

AN:

44558

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26032

East Asian (EAS)

AF:

0.0307

AC:

1217

AN:

39604

South Asian (SAS)

AF:

0.00183

AC:

157

AN:

85746

European-Finnish (FIN)

AF:

0.0000375

AC:

AN:

53340

Middle Eastern (MID)

AF:

0.000174

AC:

AN:

5750

European-Non Finnish (NFE)

AF:

0.000201

AC:

222

AN:

1104610

Other (OTH)

AF:

0.00391

AC:

235

AN:

60100

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.473

Heterozygous variant carriers

191

287

382

478

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

132

176

220

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00226

AC:

344

AN:

152204

Hom.:

Cov.:

AF XY:

0.00242

AC XY:

180

AN XY:

74416

show subpopulations

African (AFR)

AF:

0.000506

AC:

AN:

41532

American (AMR)

AF:

0.00379

AC:

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.0444

AC:

230

AN:

5184

South Asian (SAS)

AF:

0.00270

AC:

AN:

4806

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10608

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000206

AC:

AN:

68002

Other (OTH)

AF:

0.00379

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00170

Hom.:

Bravo

AF:

0.00309

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.000249

AC:

ESP6500EA

AF:

0.000120

AC:

ExAC

AF:

0.00466

AC:

564

Asia WGS

AF:

0.0180

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Jul 08, 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. -

Feb 13, 2015

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Nemaline myopathy 2

Benign:3

Sep 16, 2020

Natera, Inc.

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 13, 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:2

Apr 24, 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.23009G>A (p.Gly7670Glu) variant involves the alteration of a conserved nucleotide. 2/3 in silico tools predict a damaging outcome for this variant (SNPsandGO not captured due to low reliability index). 4/5 splice prediction tools predict strenthening of the canonical splicing site. However, these predictions have yet to be confirmed by functional studies. This variant was found in 556/106474 control chromosomes (12 homozygotes), predominantly observed in the East Asian subpopulation at a frequency of 0.049128 (383/7796). This frequency is about 14 times the estimated maximal expected allele frequency of a pathogenic NEB variant (0.0035355), suggesting this is likely a benign polymorphism found primarily in the populations of East Asian origin. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as benign/likely benign. The variant of interest has not, to our knowledge, been reported in affected individuals via publications and/or reputable databases/clinical diagnostic laboratories; nor evaluated for functional impact by in vivo/vitro studies. Taken together, this variant is classified as benign. -

Jun 27, 2019

Athena Diagnostics

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

0.16

BayesDel_addAF

Benign

-0.31

BayesDel_noAF

Benign

-0.18

CADD

Benign

(source)

DANN

Benign

0.75

DEOGEN2

Benign

0.0065

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

Eigen

Uncertain

0.28

Eigen_PC

Uncertain

0.38

FATHMM_MKL

Uncertain

0.82

LIST_S2

Benign

0.83

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

MetaRNN

Benign

0.0057

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

MetaSVM

Benign

-1.1

MutationAssessor

Benign

-1.8

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

PhyloP100

5.0

PrimateAI

Uncertain

0.61

PROVEAN

Benign

0.15

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

REVEL

Benign

0.21

Sift

Benign

1.0

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

Sift4G

Benign

1.0

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

Polyphen

0.0080

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

Vest4

0.16

MVP

0.60

MPC

0.079

ClinPred

0.017

GERP RS

5.6

Varity_R

0.099

gMVP

0.096

Mutation Taster

=66/34

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.0039

dbscSNV1_RF

Benign

0.038

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over