rs115394251

chr2-151501528-T-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_001164507.2(NEB):c.23929-45A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0113 in 1,155,992 control chromosomes in the GnomAD database, including 657 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.017 (107 hom., cov: 32)
  • Exomes 𝑓: 0.011 (550 hom.)
• Consequence: NEB NM_001164507.2 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.00

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 2-151501528-T-C is Benign according to our data. Variant chr2-151501528-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 257800.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.136 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NEB	NM_001164507.2	c.23929-45A>G		intron_variant		ENST00000427231.7
NEB	NM_001164508.2	c.23929-45A>G		intron_variant		ENST00000397345.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NEB	ENST00000397345.8	c.23929-45A>G		intron_variant		5	NM_001164508.2	P5
NEB	ENST00000427231.7	c.23929-45A>G		intron_variant		5	NM_001164507.2	A2

Frequencies

GnomAD3 genomes AF: 0.0163 AC: 2483 AN: 152154 Hom.: 98 Cov.: 32

Gnomad AFR AF: 0.0186

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00851

Gnomad ASJ AF: 0.0314

Gnomad EAS AF: 0.144

Gnomad SAS AF: 0.105

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.00231

Gnomad OTH AF: 0.0258

GnomAD3 exomes AF: 0.0244 AC: 1865 AN: 76294 Hom.: 106 AF XY: 0.0280 AC XY: 1145 AN XY: 40896

Gnomad AFR exome AF: 0.0159

Gnomad AMR exome AF: 0.00376

Gnomad ASJ exome AF: 0.0346

Gnomad EAS exome AF: 0.144

Gnomad SAS exome AF: 0.0937

Gnomad FIN exome AF: 0.000224

Gnomad NFE exome AF: 0.00243

Gnomad OTH exome AF: 0.0157

GnomAD4 exome AF: 0.0105 AC: 10558 AN: 1003720 Hom.: 550 Cov.: 13 AF XY: 0.0116 AC XY: 5660 AN XY: 488514

Gnomad4 AFR exome AF: 0.0171

Gnomad4 AMR exome AF: 0.00326

Gnomad4 ASJ exome AF: 0.0317

Gnomad4 EAS exome AF: 0.137

Gnomad4 SAS exome AF: 0.0892

Gnomad4 FIN exome AF: 0.000661

Gnomad4 NFE exome AF: 0.00176

Gnomad4 OTH exome AF: 0.0219

GnomAD4 genome AF: 0.0165 AC: 2517 AN: 152272 Hom.: 107 Cov.: 32 AF XY: 0.0182 AC XY: 1358 AN XY: 74450

Gnomad4 AFR AF: 0.0188

Gnomad4 AMR AF: 0.00850

Gnomad4 ASJ AF: 0.0314

Gnomad4 EAS AF: 0.145

Gnomad4 SAS AF: 0.106

Gnomad4 FIN AF: 0.0000942

Gnomad4 NFE AF: 0.00231

Gnomad4 OTH AF: 0.0354

Alfa AF: 0.0102 Hom.: 8

Bravo AF: 0.0151

Asia WGS AF: 0.149 AC: 517 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
Cadd	Benign	8.4
Dann	Benign	0.69

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs115394251; hg19: chr2-152358042; COSMIC: COSV51419673; COSMIC: COSV51419673;