rs13031275

Positions:

• chr2-151489980-A-C

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.25395T>G​(p.Ser8465=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0544 in 1,590,030 control chromosomes in the GnomAD database, including 2,772 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.038 (154 hom., cov: 32)
  • Exomes 𝑓: 0.056 (2618 hom.)
• Consequence: NEB NM_001164508.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -0.804

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]

RIF1 (HGNC:23207): (replication timing regulatory factor 1) This gene encodes a protein that shares homology with the yeast teleomere binding protein, Rap1 interacting factor 1. This protein localizes to aberrant telomeres may be involved in DNA repair. Alternate splicing results in multiple transcript variants. [provided by RefSeq, Apr 2010]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.53).
• BP6: Variant 2-151489980-A-C is Benign according to our data. Variant chr2-151489980-A-C is described in ClinVar as [Benign]. Clinvar id is 129735.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-151489980-A-C is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-0.804 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0592 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NEB	NM_001164507.2	c.25395T>G	p.Ser8465=	synonymous_variant	181/182	ENST00000427231.7	NP_001157979.2
NEB	NM_001164508.2	c.25395T>G	p.Ser8465=	synonymous_variant	181/182	ENST00000397345.8	NP_001157980.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NEB	ENST00000397345.8	c.25395T>G	p.Ser8465=	synonymous_variant	181/182	5	NM_001164508.2	ENSP00000380505	P5
NEB	ENST00000427231.7	c.25395T>G	p.Ser8465=	synonymous_variant	181/182	5	NM_001164507.2	ENSP00000416578	A2

Frequencies

GnomAD3 genomes AF: 0.0379 AC: 5775 AN: 152176 Hom.: 154 Cov.: 32

Gnomad AFR AF: 0.0119

Gnomad AMI AF: 0.0921

Gnomad AMR AF: 0.0268

Gnomad ASJ AF: 0.0493

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.0176

Gnomad FIN AF: 0.0287

Gnomad MID AF: 0.0475

Gnomad NFE AF: 0.0607

Gnomad OTH AF: 0.0373

GnomAD3 exomes AF: 0.0418 AC: 10392 AN: 248880 Hom.: 298 AF XY: 0.0425 AC XY: 5741 AN XY: 134998

Gnomad AFR exome AF: 0.0120

Gnomad AMR exome AF: 0.0217

Gnomad ASJ exome AF: 0.0451

Gnomad EAS exome AF: 0.0000557

Gnomad SAS exome AF: 0.0217

Gnomad FIN exome AF: 0.0311

Gnomad NFE exome AF: 0.0657

Gnomad OTH exome AF: 0.0437

GnomAD4 exome AF: 0.0561 AC: 80722 AN: 1437736 Hom.: 2618 Cov.: 29 AF XY: 0.0554 AC XY: 39726 AN XY: 716786

Gnomad4 AFR exome AF: 0.00966

Gnomad4 AMR exome AF: 0.0232

Gnomad4 ASJ exome AF: 0.0458

Gnomad4 EAS exome AF: 0.0000758

Gnomad4 SAS exome AF: 0.0219

Gnomad4 FIN exome AF: 0.0336

Gnomad4 NFE exome AF: 0.0657

Gnomad4 OTH exome AF: 0.0456

GnomAD4 genome AF: 0.0379 AC: 5772 AN: 152294 Hom.: 154 Cov.: 32 AF XY: 0.0352 AC XY: 2621 AN XY: 74474

Gnomad4 AFR AF: 0.0119

Gnomad4 AMR AF: 0.0267

Gnomad4 ASJ AF: 0.0493

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.0174

Gnomad4 FIN AF: 0.0287

Gnomad4 NFE AF: 0.0607

Gnomad4 OTH AF: 0.0369

Alfa AF: 0.0581 Hom.: 478

Bravo AF: 0.0375

Asia WGS AF: 0.00953 AC: 34 AN: 3478

EpiCase AF: 0.0599

EpiControl AF: 0.0622

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

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	Feb 26, 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	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Nov 26, 2014	p.Ser8500Ser in exon 182 of NEB: This variant is not expected to have clinical s ignificance because it has been identified in 6.5% (530/8194) of European Americ an chromosomes by the NHLBI Exome Sequencing Project (http://evs.gs.washington.e du/EVS/; dbSNP rs13031275). -

Nemaline myopathy 2 Benign:3

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	- -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

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- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.53
CADD	Benign	1.9
DANN	Benign	0.75

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: rs13031275; hg19: chr2-152346494;