rs34555492

Positions:

chr2-151540718-G-A

Variant summary

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

The NM_001164508.2(NEB):c.20766C>T(p.Asp6922=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0194 in 1,613,436 control chromosomes in the GnomAD database, including 400 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.013 ( 23 hom., cov: 32)

Exomes 𝑓: 0.020 ( 377 hom. )

Consequence

NEB
NM_001164508.2 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: -2.22

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:

LOC124906081 (HGNC:):

LOC124906081 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=-0.75).

BP6

Variant 2-151540718-G-A is Benign according to our data. Variant chr2-151540718-G-A is described in ClinVar as [Benign]. Clinvar id is 129723.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-151540718-G-A is described in Lovd as [Likely_benign]. Variant chr2-151540718-G-A is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=-2.22 with no splicing effect.

BS1

Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.0131 (1997/152210) while in subpopulation SAS AF= 0.038 (183/4820). AF 95% confidence interval is 0.0335. There are 23 homozygotes in gnomad4. There are 928 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 23 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
NEB	NM_001164507.2 linkuse as main transcript	c.20766C>T	p.Asp6922=	synonymous_variant	137/182	ENST00000427231.7	NP_001157979.2
NEB	NM_001164508.2 linkuse as main transcript	c.20766C>T	p.Asp6922=	synonymous_variant	137/182	ENST00000397345.8	NP_001157980.2
LOC124906081	XR_007087266.1 linkuse as main transcript	n.2943G>A		non_coding_transcript_exon_variant	2/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NEB	ENST00000397345.8 linkuse as main transcript	c.20766C>T	p.Asp6922=	synonymous_variant	137/182	5	NM_001164508.2	ENSP00000380505	P5	P20929-2
NEB	ENST00000427231.7 linkuse as main transcript	c.20766C>T	p.Asp6922=	synonymous_variant	137/182	5	NM_001164507.2	ENSP00000416578	A2	P20929-3

Frequencies

GnomAD3 genomes

AF:

0.0131

AC:

2000

AN:

152092

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00418

Gnomad AMI

AF:

0.00877

Gnomad AMR

AF:

0.00819

Gnomad ASJ

AF:

0.00173

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.0381

Gnomad FIN

AF:

0.00462

Gnomad MID

AF:

0.0285

Gnomad NFE

AF:

0.0209

Gnomad OTH

AF:

0.0105

GnomAD3 exomes

AF:

0.0154

AC:

3840

AN:

248722

Hom.:

AF XY:

0.0174

AC XY:

2346

AN XY:

134906

show subpopulations

Gnomad AFR exome

AF:

0.00362

Gnomad AMR exome

AF:

0.00467

Gnomad ASJ exome

AF:

0.00109

Gnomad EAS exome

AF:

0.0000557

Gnomad SAS exome

AF:

0.0408

Gnomad FIN exome

AF:

0.00539

Gnomad NFE exome

AF:

0.0193

Gnomad OTH exome

AF:

0.0123

GnomAD4 exome

AF:

0.0201

AC:

29301

AN:

1461226

Hom.:

377

Cov.:

AF XY:

0.0206

AC XY:

14997

AN XY:

726904

show subpopulations

Gnomad4 AFR exome

AF:

0.00350

Gnomad4 AMR exome

AF:

0.00476

Gnomad4 ASJ exome

AF:

0.000727

Gnomad4 EAS exome

AF:

0.000151

Gnomad4 SAS exome

AF:

0.0397

Gnomad4 FIN exome

AF:

0.00648

Gnomad4 NFE exome

AF:

0.0216

Gnomad4 OTH exome

AF:

0.0184

GnomAD4 genome

AF:

0.0131

AC:

1997

AN:

152210

Hom.:

Cov.:

AF XY:

0.0125

AC XY:

928

AN XY:

74418

show subpopulations

Gnomad4 AFR

AF:

0.00417

Gnomad4 AMR

AF:

0.00818

Gnomad4 ASJ

AF:

0.00173

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.0380

Gnomad4 FIN

AF:

0.00462

Gnomad4 NFE

AF:

0.0209

Gnomad4 OTH

AF:

0.0104

Alfa

AF:

0.0166

Hom.:

Bravo

AF:

0.0120

Asia WGS

AF:

0.00866

AC:

AN:

3478

EpiCase

AF:

0.0184

EpiControl

AF:

0.0173

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	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. -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2016	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. -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 22, 2019	Variant summary: NEB c.20766C>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 0.015 in 280110 control chromosomes in the gnomAD database, including 68 homozygotes. The observed variant frequency is approximately 4-folds higher than 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. Three ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant twice as benign and once as uncertain significance. Based on the evidence outlined above, the variant was classified as benign. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Nemaline myopathy 2

Benign:4

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	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. -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	May 18, 2021	- -

not provided

Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

- -

Arthrogryposis multiplex congenita 6

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 10, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.75

CADD

Benign

0.052

DANN

Benign

0.49

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