2-151664582-C-T

Variant names:

• chr2-151664582-C-T
• rs10170273
• NM_001164507.2:c.5370G>A

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: -0.319

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]

ACMG classification

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 rank	MANE	Protein	UniProt
NEB	NM_001164507.2	c.5370G>A	p.Glu1790Glu	synonymous_variant	Exon 44 of 182	ENST00000427231.7	NP_001157979.2
NEB	NM_001164508.2	c.5370G>A	p.Glu1790Glu	synonymous_variant	Exon 44 of 182	ENST00000397345.8	NP_001157980.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NEB	ENST00000397345.8	c.5370G>A	p.Glu1790Glu	synonymous_variant	Exon 44 of 182	5	NM_001164508.2	ENSP00000380505.3
NEB	ENST00000427231.7	c.5370G>A	p.Glu1790Glu	synonymous_variant	Exon 44 of 182	5	NM_001164507.2	ENSP00000416578.2
NEB	ENST00000409198.5	c.5370G>A	p.Glu1790Glu	synonymous_variant	Exon 44 of 150	5		ENSP00000386259.1

Frequencies

GnomAD3 genomes AF: 0.304 AC: 46248 AN: 152036 Hom.: 10216 Cov.: 33

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

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.: 32 AF XY: 0.197 AC XY: 142009 AN XY: 721562

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.: 33 AF XY: 0.302 AC XY: 22480 AN XY: 74382

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

Submissions by phenotype

not specified Benign:4

-

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

- -

Nov 26, 2014

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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). -

Jan 05, 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. -

Nemaline myopathy 2 Benign:4

Sep 16, 2020

Natera, Inc.

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jan 13, 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. -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:3

Feb 27, 2017

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

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Mar 07, 2019

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Arthrogryposis multiplex congenita 6 Benign:1

Jul 10, 2021

Genome-Nilou Lab

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	-0.42
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

Other links and lift over

dbSNP: rs10170273; hg19: chr2-152521096; COSMIC: COSV50874015; COSMIC: COSV50874015;