2-151664582-C-T

Position:

chr2-151664582-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BA1

The NM_001164508.2(NEB):c.5370G>A(p.Glu1790Glu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.205 in 1,604,590 control chromosomes in the GnomAD database, including 47,250 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.30 ( 10269 hom., cov: 33)

Exomes 𝑓: 0.19 ( 36981 hom. )

Consequence

NEB
NM_001164508.2 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: -0.319

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 -19 ACMG points.

BP4

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

BP6

Variant 2-151664582-C-T is Benign according to our data. Variant chr2-151664582-C-T is described in ClinVar as [Benign]. Clinvar id is 129746.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-151664582-C-T is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=-0.319 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.593 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NEB	NM_001164507.2 linkuse as main transcript	c.5370G>A	p.Glu1790Glu	synonymous_variant	44/182	ENST00000427231.7	NP_001157979.2
NEB	NM_001164508.2 linkuse as main transcript	c.5370G>A	p.Glu1790Glu	synonymous_variant	44/182	ENST00000397345.8	NP_001157980.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
NEB	ENST00000397345.8 linkuse as main transcript	c.5370G>A	p.Glu1790Glu	synonymous_variant	44/182	5	NM_001164508.2	ENSP00000380505.3	P20929-2
NEB	ENST00000427231.7 linkuse as main transcript	c.5370G>A	p.Glu1790Glu	synonymous_variant	44/182	5	NM_001164507.2	ENSP00000416578.2	P20929-3
NEB	ENST00000409198.5 linkuse as main transcript	c.5370G>A	p.Glu1790Glu	synonymous_variant	44/150	5		ENSP00000386259.1	P20929-4

Frequencies

GnomAD3 genomes

AF:

0.304

AC:

46248

AN:

152036

Hom.:

10216

Cov.:

show subpopulations

Gnomad AFR

AF:

0.599

Gnomad AMI

AF:

0.177

Gnomad AMR

AF:

0.183

Gnomad ASJ

AF:

0.261

Gnomad EAS

AF:

0.605

Gnomad SAS

AF:

0.341

Gnomad FIN

AF:

0.131

Gnomad MID

AF:

0.215

Gnomad NFE

AF:

0.159

Gnomad OTH

AF:

0.277

GnomAD3 exomes

AF:

0.235

AC:

55160

AN:

234970

Hom.:

9337

AF XY:

0.233

AC XY:

29596

AN XY:

127078

show subpopulations

Gnomad AFR exome

AF:

0.605

Gnomad AMR exome

AF:

0.132

Gnomad ASJ exome

AF:

0.246

Gnomad EAS exome

AF:

0.582

Gnomad SAS exome

AF:

0.339

Gnomad FIN exome

AF:

0.138

Gnomad NFE exome

AF:

0.154

Gnomad OTH exome

AF:

0.211

GnomAD4 exome

AF:

0.194

AC:

282020

AN:

1452434

Hom.:

36981

Cov.:

AF XY:

0.197

AC XY:

142009

AN XY:

721562

show subpopulations

Gnomad4 AFR exome

AF:

0.616

Gnomad4 AMR exome

AF:

0.139

Gnomad4 ASJ exome

AF:

0.250

Gnomad4 EAS exome

AF:

0.619

Gnomad4 SAS exome

AF:

0.333

Gnomad4 FIN exome

AF:

0.141

Gnomad4 NFE exome

AF:

0.157

Gnomad4 OTH exome

AF:

0.238

GnomAD4 genome

AF:

0.305

AC:

46355

AN:

152156

Hom.:

10269

Cov.:

AF XY:

0.302

AC XY:

22480

AN XY:

74382

show subpopulations

Gnomad4 AFR

AF:

0.599

Gnomad4 AMR

AF:

0.183

Gnomad4 ASJ

AF:

0.261

Gnomad4 EAS

AF:

0.605

Gnomad4 SAS

AF:

0.341

Gnomad4 FIN

AF:

0.131

Gnomad4 NFE

AF:

0.159

Gnomad4 OTH

AF:

0.285

Alfa

AF:

0.195

Hom.:

4939

Bravo

AF:

0.320

Asia WGS

AF:

0.542

AC:

1879

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
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	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Nov 26, 2014	p.Glu1790Glu in exon 44 of NEB: This variant is not expected to have clinical si gnificance because it has been identified in 58% (2157/3720) of African American chromosomes by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu /EVS/; dbSNP rs10170273). -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 05, 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. -

Nemaline myopathy 2

Benign:4

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 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	Jul 10, 2021	- -

not provided

Benign:3

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Feb 27, 2017	Variant summary: The NEB c.5370G>A (p.Glu1790Glu) variant involves the alteration of a non-conserved nucleotide, resulting in a synonymous change. One in silico tool, Mutation Taster, predicts a polymorphism outcome for this variant. 5/5 splice prediction tools predict no significant impact on normal splicing. ESE finder predicts that this variant may create an SF2/ASF ESE site. However, these predictions have yet to be confirmed by functional studies. This variant was found in 25704/85158 control chromosomes (4373 homozygotes) at a frequency of 0.3018389, which is approximately 85 times the estimated maximal expected allele frequency of a pathogenic NEB variant (0.0035355), suggesting this variant is likely a benign polymorphism. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as benign. The variant of interest has not, to our knowledge, been reported in affected individuals via publications nor evaluated for functional impact by in vivo/vitro studies. Taken together, this variant is classified as benign. -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Mar 07, 2019	- -

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

-0.42

CADD

Benign

2.5

DANN

Benign

0.52

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