rs184319249

chr2-151492117-T-Cchr2-151492117-T-G

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6 BP7 BS1

The NM_001164507.2(NEB):c.25038A>G(p.Gln8346=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000716 in 1,613,982 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00074 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00071 (4 hom.)
• Consequence: NEB NM_001164507.2 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:9
• Conservation: PhyloP100: 0.827

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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.56).
• BP6: Variant 2-151492117-T-C is Benign according to our data. Variant chr2-151492117-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 95124.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=3, Benign=1, Likely_benign=5}. Variant chr2-151492117-T-C is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=0.827 with no splicing effect.
• BS1: Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.000714 (1044/1461652) while in subpopulation MID AF= 0.00451 (26/5764). AF 95% confidence interval is 0.00316. There are 4 homozygotes in gnomad4_exome. There are 589 alleles in male gnomad4_exome subpopulation. Median coverage is 31. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NEB	NM_001164507.2	c.25038A>G	p.Gln8346=	synonymous_variant	178/182	ENST00000427231.7
NEB	NM_001164508.2	c.25038A>G	p.Gln8346=	synonymous_variant	178/182	ENST00000397345.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NEB	ENST00000397345.8	c.25038A>G	p.Gln8346=	synonymous_variant	178/182	5	NM_001164508.2	P5
NEB	ENST00000427231.7	c.25038A>G	p.Gln8346=	synonymous_variant	178/182	5	NM_001164507.2	A2

Frequencies

GnomAD3 genomes AF: 0.000736 AC: 112 AN: 152212 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00987

Gnomad AMR AF: 0.000981

Gnomad ASJ AF: 0.00518

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000838

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.000987 AC: 246 AN: 249134 Hom.: 1 AF XY: 0.00111 AC XY: 150 AN XY: 135160

Gnomad AFR exome AF: 0.0000646

Gnomad AMR exome AF: 0.000348

Gnomad ASJ exome AF: 0.00398

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00307

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000788

Gnomad OTH exome AF: 0.00165

GnomAD4 exome AF: 0.000714 AC: 1044 AN: 1461652 Hom.: 4 Cov.: 31 AF XY: 0.000810 AC XY: 589 AN XY: 727106

Gnomad4 AFR exome AF: 0.000239

Gnomad4 AMR exome AF: 0.000559

Gnomad4 ASJ exome AF: 0.00486

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00294

Gnomad4 FIN exome AF: 0.0000749

Gnomad4 NFE exome AF: 0.000482

Gnomad4 OTH exome AF: 0.00104

GnomAD4 genome AF: 0.000735 AC: 112 AN: 152330 Hom.: 0 Cov.: 32 AF XY: 0.000792 AC XY: 59 AN XY: 74484

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.000980

Gnomad4 ASJ AF: 0.00518

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00124

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000838

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.000913 Hom.: 0

Bravo AF: 0.000763

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00136

EpiControl AF: 0.000949

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:9

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:5

Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 29, 2013	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Mar 15, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 19, 2020	This variant is associated with the following publications: (PMID: 32403337) -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2024	NEB: BP4, BP7 -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

Nemaline myopathy 2 Uncertain:1 Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -
Uncertain significance, 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -
Likely benign, no assertion criteria provided	clinical testing	Natera, Inc.	Jan 12, 2020	- -

not specified Uncertain:1 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Nov 04, 2014	- -

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

May 23, 2023

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.56
Cadd	Benign	3.3
Dann	Benign	0.67

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: rs184319249; hg19: chr2-152348631; COSMIC: COSV99429403; COSMIC: COSV99429403;