chr2-151717467-A-G

Position:

• chr2-151717467-A-G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001164508.2(NEB):​c.771T>C​(p.Ala257Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.788 in 1,613,292 control chromosomes in the GnomAD database, including 514,625 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.68 (38781 hom., cov: 32)
  • Exomes 𝑓: 0.80 (475844 hom.)
• Consequence: NEB NM_001164508.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:15
• Conservation: PhyloP100: -0.311

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.75).
• BP6: Variant 2-151717467-A-G is Benign according to our data. Variant chr2-151717467-A-G is described in ClinVar as [Benign]. Clinvar id is 95136.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-151717467-A-G is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.311 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.828 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NEB	NM_001164507.2	c.771T>C	p.Ala257Ala	synonymous_variant	10/182	ENST00000427231.7	NP_001157979.2
NEB	NM_001164508.2	c.771T>C	p.Ala257Ala	synonymous_variant	10/182	ENST00000397345.8	NP_001157980.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NEB	ENST00000397345.8	c.771T>C	p.Ala257Ala	synonymous_variant	10/182	5	NM_001164508.2	ENSP00000380505.3
NEB	ENST00000427231.7	c.771T>C	p.Ala257Ala	synonymous_variant	10/182	5	NM_001164507.2	ENSP00000416578.2
NEB	ENST00000409198.5	c.771T>C	p.Ala257Ala	synonymous_variant	10/150	5		ENSP00000386259.1

Frequencies

GnomAD3 genomes AF: 0.681 AC: 103529 AN: 152040 Hom.: 38775 Cov.: 32

Gnomad AFR AF: 0.357

Gnomad AMI AF: 0.842

Gnomad AMR AF: 0.811

Gnomad ASJ AF: 0.727

Gnomad EAS AF: 0.458

Gnomad SAS AF: 0.650

Gnomad FIN AF: 0.860

Gnomad MID AF: 0.763

Gnomad NFE AF: 0.834

Gnomad OTH AF: 0.724

GnomAD3 exomes AF: 0.755 AC: 188045 AN: 249044 Hom.: 74061 AF XY: 0.757 AC XY: 102273 AN XY: 135106

Gnomad AFR exome AF: 0.339

Gnomad AMR exome AF: 0.863

Gnomad ASJ exome AF: 0.737

Gnomad EAS exome AF: 0.475

Gnomad SAS exome AF: 0.645

Gnomad FIN exome AF: 0.852

Gnomad NFE exome AF: 0.835

Gnomad OTH exome AF: 0.788

GnomAD4 exome AF: 0.799 AC: 1167823 AN: 1461134 Hom.: 475844 Cov.: 48 AF XY: 0.796 AC XY: 578963 AN XY: 726886

Gnomad4 AFR exome AF: 0.345

Gnomad4 AMR exome AF: 0.856

Gnomad4 ASJ exome AF: 0.739

Gnomad4 EAS exome AF: 0.439

Gnomad4 SAS exome AF: 0.655

Gnomad4 FIN exome AF: 0.850

Gnomad4 NFE exome AF: 0.836

Gnomad4 OTH exome AF: 0.760

GnomAD4 genome AF: 0.681 AC: 103547 AN: 152158 Hom.: 38781 Cov.: 32 AF XY: 0.684 AC XY: 50863 AN XY: 74386

Gnomad4 AFR AF: 0.356

Gnomad4 AMR AF: 0.811

Gnomad4 ASJ AF: 0.727

Gnomad4 EAS AF: 0.458

Gnomad4 SAS AF: 0.650

Gnomad4 FIN AF: 0.860

Gnomad4 NFE AF: 0.834

Gnomad4 OTH AF: 0.716

Alfa AF: 0.793 Hom.: 63138

Bravo AF: 0.665

Asia WGS AF: 0.498 AC: 1736 AN: 3478

EpiCase AF: 0.839

EpiControl AF: 0.834

ClinVar

Significance: Benign

Submissions summary: Benign:15

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:6

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, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 11, 2013	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Nov 26, 2014	p.Ala257Ala in exon 10 of NEB: This variant is not expected to have clinical sig nificance because it has been identified in 83% (6805/8228) of European American chromosomes by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu /EVS/; dbSNP rs4611637). -
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:5

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 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, 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.771T>C (p.Ala257Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide, which 4/5 splice prediction tools predict no significant impact on normal splicing. The variant of interest was observed in the large, broad control population, ExAC, with an allele frequency of 0.7437533 (89655/120544 (34969 homozygotes)), which indicates that the C allele is the major allele found in the general population. In addition, multiple clinical diagnostic laboratories classify the variant as Benign. Therefore, the variant of interest has been classified as Benign. -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Feb 21, 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	-0.75
CADD	Benign	0.33
DANN	Benign	0.54

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: rs4611637; hg19: chr2-152573981; COSMIC: COSV50869840;