rs61730771

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_001164508.2(NEB):c.8466C>T(p.His2822His) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0197 in 1,613,806 control chromosomes in the GnomAD database, including 458 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.025 ( 63 hom., cov: 32)

Exomes 𝑓: 0.019 ( 395 hom. )

Consequence

NEB
NM_001164508.2 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:12

Conservation

PhyloP100: -2.48

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 Benign. Variant got -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.58).

BP6

Variant 2-151640574-G-A is Benign according to our data. Variant chr2-151640574-G-A is described in ClinVar as [Benign]. Clinvar id is 129759.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-151640574-G-A is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=-2.48 with no splicing effect.

BS1

Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.0247 (3755/152116) while in subpopulation SAS AF= 0.0455 (219/4816). AF 95% confidence interval is 0.0405. There are 63 homozygotes in gnomad4. There are 1832 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 63 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NEB	NM_001164507.2 link	c.8466C>T	p.His2822His	synonymous_variant	Exon 61 of 182	ENST00000427231.7	NP_001157979.2
NEB	NM_001164508.2 link	c.8466C>T	p.His2822His	synonymous_variant	Exon 61 of 182	ENST00000397345.8	NP_001157980.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
NEB	ENST00000397345.8 link	c.8466C>T	p.His2822His	synonymous_variant	Exon 61 of 182	5	NM_001164508.2	ENSP00000380505.3	P20929-2
NEB	ENST00000427231.7 link	c.8466C>T	p.His2822His	synonymous_variant	Exon 61 of 182	5	NM_001164507.2	ENSP00000416578.2	P20929-3
NEB	ENST00000409198.5 link	c.8466C>T	p.His2822His	synonymous_variant	Exon 61 of 150	5		ENSP00000386259.1	P20929-4

Frequencies

GnomAD3 genomes

AF:

0.0246

AC:

3744

AN:

151998

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0415

Gnomad AMI

AF:

0.0241

Gnomad AMR

AF:

0.0159

Gnomad ASJ

AF:

0.0427

Gnomad EAS

AF:

0.00444

Gnomad SAS

AF:

0.0446

Gnomad FIN

AF:

0.0123

Gnomad MID

AF:

0.0411

Gnomad NFE

AF:

0.0173

Gnomad OTH

AF:

0.0273

GnomAD3 exomes

AF:

0.0211

AC:

5256

AN:

249214

Hom.:

AF XY:

0.0223

AC XY:

3008

AN XY:

135190

show subpopulations

Gnomad AFR exome

AF:

0.0462

Gnomad AMR exome

AF:

0.00857

Gnomad ASJ exome

AF:

0.0467

Gnomad EAS exome

AF:

0.00406

Gnomad SAS exome

AF:

0.0459

Gnomad FIN exome

AF:

0.0130

Gnomad NFE exome

AF:

0.0168

Gnomad OTH exome

AF:

0.0200

GnomAD4 exome

AF:

0.0192

AC:

27994

AN:

1461690

Hom.:

395

Cov.:

AF XY:

0.0200

AC XY:

14566

AN XY:

727130

show subpopulations

Gnomad4 AFR exome

AF:

0.0456

Gnomad4 AMR exome

AF:

0.00953

Gnomad4 ASJ exome

AF:

0.0468

Gnomad4 EAS exome

AF:

0.00186

Gnomad4 SAS exome

AF:

0.0473

Gnomad4 FIN exome

AF:

0.0124

Gnomad4 NFE exome

AF:

0.0165

Gnomad4 OTH exome

AF:

0.0243

GnomAD4 genome

AF:

0.0247

AC:

3755

AN:

152116

Hom.:

Cov.:

AF XY:

0.0246

AC XY:

1832

AN XY:

74346

show subpopulations

Gnomad4 AFR

AF:

0.0415

Gnomad4 AMR

AF:

0.0158

Gnomad4 ASJ

AF:

0.0427

Gnomad4 EAS

AF:

0.00445

Gnomad4 SAS

AF:

0.0455

Gnomad4 FIN

AF:

0.0123

Gnomad4 NFE

AF:

0.0173

Gnomad4 OTH

AF:

0.0270

Alfa

AF:

0.0181

Hom.:

Bravo

AF:

0.0250

Asia WGS

AF:

0.0410

AC:

142

AN:

3478

EpiCase

AF:

0.0178

EpiControl

AF:

0.0200

ClinVar

Significance: Benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:6

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jan 13, 2015

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

p.His2822His in exon 61 of NEB: This variant is not expected to have clinical si gnificance because it does not alter an amino acid residue and is not located wi thin the splice consensus sequence. It has been identified in 4.1% (162/3930) of African American chromosomes from a broad population by the NHLBI Exome Sequenc ing Project (http://evs.gs.washington.edu/EVS; dbSNP rs61730771). -

Mar 12, 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. -

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. -

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 01, 2019

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

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: NEB c.8466C>T alters a non-conserved nucleotide resulting in a synonymous change. 5/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.021 in 277116 control chromosomes in the gnomAD database, including 92 homozygotes. The observed variant frequency is approximately 6 fold of the estimated maximal expected allele frequency for a pathogenic variant in NEB causing Nemaline Myopathy 2 phenotype (0.0035), strongly suggesting that the variant is benign. To our knowledge, no occurrence of c.8466C>T in individuals affected with Nemaline Myopathy 2 and no experimental evidence demonstrating its impact on protein function have been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as benign. -

not provided

Benign:3

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Mar 04, 2019

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nemaline myopathy 2

Benign:3

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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.58

CADD

Benign

0.68

DANN

Benign

0.50

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