rs114218081

Variant names:

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 0P and 18B. BP4_ModerateBP6_Very_StrongBS1BS2

The NM_001164508.2(NEB):c.21382T>C(p.Leu7128Leu) variant causes a synonymous change. The variant allele was found at a frequency of 0.0215 in 1,551,314 control chromosomes in the GnomAD database, including 436 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.026 ( 66 hom., cov: 33)

Exomes 𝑓: 0.021 ( 370 hom. )

Consequence

NEB
NM_001164508.2 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 3.75

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 -18 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.42).

BP6

Variant 2-151533477-A-G is Benign according to our data. Variant chr2-151533477-A-G is described in ClinVar as [Benign]. Clinvar id is 257788.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-151533477-A-G is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0259 (3943/152358) while in subpopulation AFR AF= 0.0435 (1807/41576). AF 95% confidence interval is 0.0418. There are 66 homozygotes in gnomad4. There are 1957 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 66 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NEB	NM_001164508.2 link	c.21382T>C	p.Leu7128Leu	synonymous_variant	Exon 143 of 182	ENST00000397345.8	NP_001157980.2
NEB	NM_001164507.2 link	c.21417+738T>C		intron_variant	Intron 143 of 181	ENST00000427231.7	NP_001157979.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NEB	ENST00000397345.8 link	c.21382T>C	p.Leu7128Leu	synonymous_variant	Exon 143 of 182	5	NM_001164508.2	ENSP00000380505.3		P20929-2
NEB	ENST00000427231.7 link	c.21417+738T>C		intron_variant	Intron 143 of 181	5	NM_001164507.2	ENSP00000416578.2		P20929-3

Frequencies

GnomAD3 genomes

AF:

0.0258

AC:

3932

AN:

152240

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0433

Gnomad AMI

AF:

0.00110

Gnomad AMR

AF:

0.0121

Gnomad ASJ

AF:

0.0282

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.00538

Gnomad FIN

AF:

0.0405

Gnomad MID

AF:

0.0222

Gnomad NFE

AF:

0.0196

Gnomad OTH

AF:

0.0248

GnomAD3 exomes

AF:

0.0183

AC:

2883

AN:

157248

Hom.:

AF XY:

0.0172

AC XY:

1433

AN XY:

83098

show subpopulations

Gnomad AFR exome

AF:

0.0411

Gnomad AMR exome

AF:

0.00915

Gnomad ASJ exome

AF:

0.0227

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00667

Gnomad FIN exome

AF:

0.0364

Gnomad NFE exome

AF:

0.0208

Gnomad OTH exome

AF:

0.0219

GnomAD4 exome

AF:

0.0211

AC:

29472

AN:

1398956

Hom.:

370

Cov.:

AF XY:

0.0204

AC XY:

14071

AN XY:

690012

show subpopulations

Gnomad4 AFR exome

AF:

0.0453

Gnomad4 AMR exome

AF:

0.0103

Gnomad4 ASJ exome

AF:

0.0231

Gnomad4 EAS exome

AF:

0.0000280

Gnomad4 SAS exome

AF:

0.00713

Gnomad4 FIN exome

AF:

0.0351

Gnomad4 NFE exome

AF:

0.0219

Gnomad4 OTH exome

AF:

0.0201

GnomAD4 genome

AF:

0.0259

AC:

3943

AN:

152358

Hom.:

Cov.:

AF XY:

0.0263

AC XY:

1957

AN XY:

74504

show subpopulations

Gnomad4 AFR

AF:

0.0435

Gnomad4 AMR

AF:

0.0121

Gnomad4 ASJ

AF:

0.0282

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00538

Gnomad4 FIN

AF:

0.0405

Gnomad4 NFE

AF:

0.0197

Gnomad4 OTH

AF:

0.0246

Alfa

AF:

0.0243

Hom.:

Bravo

AF:

0.0253

Asia WGS

AF:

0.00491

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Mar 29, 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. -

Mar 07, 2016

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 01, 2022

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

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nemaline myopathy 2

Benign:2

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

- -

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.42

CADD

Benign

7.6

DANN

Benign

0.82

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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