rs34368668

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.23495C>T(p.Thr7832Ile) variant causes a missense change. The variant allele was found at a frequency of 0.00212 in 1,611,056 control chromosomes in the GnomAD database, including 60 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.010 ( 27 hom., cov: 32)

Exomes 𝑓: 0.0013 ( 33 hom. )

Consequence

NEB
NM_001164507.2 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 3.61

Publications

6 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=0.0067389607).

BP6

Variant 2-151506970-G-A is Benign according to our data. Variant chr2-151506970-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 129733.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0104 (1580/152256) while in subpopulation AFR AF = 0.0361 (1500/41544). AF 95% confidence interval is 0.0346. There are 27 homozygotes in GnomAd4. There are 739 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 27 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NEB	NM_001164507.2 link	c.23495C>T	p.Thr7832Ile	missense_variant	Exon 163 of 182	ENST00000427231.7	NP_001157979.2
NEB	NM_001164508.2 link	c.23495C>T	p.Thr7832Ile	missense_variant	Exon 163 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.23495C>T	p.Thr7832Ile	missense_variant	Exon 163 of 182	5	NM_001164508.2	ENSP00000380505.3		P20929-2
NEB	ENST00000427231.7 link	c.23495C>T	p.Thr7832Ile	missense_variant	Exon 163 of 182	5	NM_001164507.2	ENSP00000416578.2		P20929-3

Frequencies

GnomAD3 genomes

AF:

0.0104

AC:

1577

AN:

152138

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0361

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00314

Gnomad ASJ

AF:

0.00288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000176

Gnomad OTH

AF:

0.00430

GnomAD2 exomes

AF:

0.00281

AC:

700

AN:

248736

AF XY:

0.00233

show subpopulations

Gnomad AFR exome

AF:

0.0373

Gnomad AMR exome

AF:

0.00206

Gnomad ASJ exome

AF:

0.00219

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000169

Gnomad OTH exome

AF:

0.00182

GnomAD4 exome

AF:

0.00126

AC:

1838

AN:

1458800

Hom.:

Cov.:

AF XY:

0.00108

AC XY:

785

AN XY:

725872

show subpopulations

African (AFR)

AF:

0.0395

AC:

1318

AN:

33370

American (AMR)

AF:

0.00237

AC:

106

AN:

44708

Ashkenazi Jewish (ASJ)

AF:

0.00280

AC:

AN:

26108

East Asian (EAS)

AF:

0.00

AC:

AN:

39566

South Asian (SAS)

AF:

0.0000348

AC:

AN:

86180

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53042

Middle Eastern (MID)

AF:

0.00219

AC:

AN:

5488

European-Non Finnish (NFE)

AF:

0.000167

AC:

185

AN:

1110092

Other (OTH)

AF:

0.00234

AC:

141

AN:

60246

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.447

Heterozygous variant carriers

150

226

301

376

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:

0.0104

AC:

1580

AN:

152256

Hom.:

Cov.:

AF XY:

0.00993

AC XY:

739

AN XY:

74444

show subpopulations

African (AFR)

AF:

0.0361

AC:

1500

AN:

41544

American (AMR)

AF:

0.00314

AC:

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.00288

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5188

South Asian (SAS)

AF:

0.000207

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10602

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000176

AC:

AN:

68008

Other (OTH)

AF:

0.00425

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

160

239

319

399

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.00416

Hom.:

Bravo

AF:

0.0120

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.0339

AC:

123

ESP6500EA

AF:

0.000861

AC:

ExAC

AF:

0.00344

AC:

415

Asia WGS

AF:

0.000867

AC:

AN:

3474

EpiCase

AF:

0.000382

EpiControl

AF:

0.000415

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Mar 11, 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. -

Oct 16, 2024

Athena Diagnostics

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. -

not provided

Benign:2

Oct 14, 2016

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Nemaline myopathy 2

Benign:2

Jan 29, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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 was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -

Nemaline myopathy 2;C5543431:Arthrogryposis multiplex congenita 6

Benign:1

Dec 03, 2021

Fulgent Genetics, Fulgent Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.26

BayesDel_addAF

Benign

-0.30

BayesDel_noAF

Benign

-0.17

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.086

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

Eigen

Uncertain

0.42

Eigen_PC

Uncertain

0.47

FATHMM_MKL

Uncertain

0.94

LIST_S2

Benign

0.66

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

MetaRNN

Benign

0.0067

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

MetaSVM

Benign

-0.89

MutationAssessor

Uncertain

2.0

M;.;.;.;M;.;.;.;.

PhyloP100

3.6

PrimateAI

Uncertain

0.65

PROVEAN

Uncertain

-3.2

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

REVEL

Benign

0.17

Sift

Uncertain

0.022

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

Sift4G

Uncertain

0.0020

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

Polyphen

1.0

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

Vest4

0.25

MVP

0.53

MPC

0.10

ClinPred

0.030

GERP RS

5.2

PromoterAI

-0.024

Neutral

(source)

Varity_R

0.27

gMVP

0.79

Mutation Taster

=87/13

polymorphism

(source)

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

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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