rs115631125

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.19056G>T(p.Thr6352Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00592 in 1,608,264 control chromosomes in the GnomAD database, including 66 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0039 ( 3 hom., cov: 32)

Exomes 𝑓: 0.0061 ( 63 hom. )

Consequence

NEB
NM_001164508.2 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12

Conservation

PhyloP100: -5.15

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=-0.77).

BP6

Variant 2-151561253-C-A is Benign according to our data. Variant chr2-151561253-C-A is described in ClinVar as [Likely_benign]. Clinvar id is 129716.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-151561253-C-A is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=-5.15 with no splicing effect.

BS1

Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00395 (601/152260) while in subpopulation SAS AF= 0.0145 (70/4820). AF 95% confidence interval is 0.0118. There are 3 homozygotes in gnomad4. There are 307 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NEB	NM_001164507.2 link	c.19056G>T	p.Thr6352Thr	synonymous_variant	Exon 122 of 182	ENST00000427231.7	NP_001157979.2
NEB	NM_001164508.2 link	c.19056G>T	p.Thr6352Thr	synonymous_variant	Exon 122 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.19056G>T	p.Thr6352Thr	synonymous_variant	Exon 122 of 182	5	NM_001164508.2	ENSP00000380505.3		P20929-2
NEB	ENST00000427231.7 link	c.19056G>T	p.Thr6352Thr	synonymous_variant	Exon 122 of 182	5	NM_001164507.2	ENSP00000416578.2		P20929-3

Frequencies

GnomAD3 genomes

AF:

0.00396

AC:

602

AN:

152142

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00123

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00282

Gnomad ASJ

AF:

0.00922

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.0143

Gnomad FIN

AF:

0.00160

Gnomad MID

AF:

0.0222

Gnomad NFE

AF:

0.00532

Gnomad OTH

AF:

0.00955

GnomAD3 exomes

AF:

0.00575

AC:

1381

AN:

240254

Hom.:

AF XY:

0.00656

AC XY:

853

AN XY:

130022

show subpopulations

Gnomad AFR exome

AF:

0.000876

Gnomad AMR exome

AF:

0.00301

Gnomad ASJ exome

AF:

0.0106

Gnomad EAS exome

AF:

0.000115

Gnomad SAS exome

AF:

0.0149

Gnomad FIN exome

AF:

0.00242

Gnomad NFE exome

AF:

0.00583

Gnomad OTH exome

AF:

0.00679

GnomAD4 exome

AF:

0.00612

AC:

8913

AN:

1456004

Hom.:

Cov.:

AF XY:

0.00650

AC XY:

4705

AN XY:

723712

show subpopulations

Gnomad4 AFR exome

AF:

0.00117

Gnomad4 AMR exome

AF:

0.00291

Gnomad4 ASJ exome

AF:

0.00912

Gnomad4 EAS exome

AF:

0.0000506

Gnomad4 SAS exome

AF:

0.0166

Gnomad4 FIN exome

AF:

0.00330

Gnomad4 NFE exome

AF:

0.00586

Gnomad4 OTH exome

AF:

0.00617

GnomAD4 genome

AF:

0.00395

AC:

601

AN:

152260

Hom.:

Cov.:

AF XY:

0.00412

AC XY:

307

AN XY:

74442

show subpopulations

Gnomad4 AFR

AF:

0.00123

Gnomad4 AMR

AF:

0.00281

Gnomad4 ASJ

AF:

0.00922

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.0145

Gnomad4 FIN

AF:

0.00160

Gnomad4 NFE

AF:

0.00532

Gnomad4 OTH

AF:

0.00898

Alfa

AF:

0.00591

Hom.:

Bravo

AF:

0.00389

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:6

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. -

May 11, 2021

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 27, 2017

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. -

Jan 23, 2014

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

- -

Jan 25, 2025

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:3

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Likely 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

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

- -

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

May 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

NEB: BP4, BP7, BS1, BS2 -

Nemaline myopathy 2;C5543431:Arthrogryposis multiplex congenita 6

Benign:1

Oct 19, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.77

CADD

Benign

0.047

DANN

Benign

0.32

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.050

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