chr2-151519013-C-T

Variant names:

• chr2-151519013-C-T
• rs201688876
• NM_001164507.2:c.22647G>A

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_Moderate BP6 BP7 BS2_Supporting

The ENST00000397345.8(NEB):​c.22647G>A​(p.Glu7549Glu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000484 in 1,613,740 control chromosomes in the GnomAD database, including 2 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 0.00028 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00051 (2 hom.)
• Consequence: NEB ENST00000397345.8 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:4
• Conservation: PhyloP100: -0.0750
• Publications: 1 publications found

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

Our verdict: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (REVEL=0.15).
• BP6: Variant 2-151519013-C-T is Benign according to our data. Variant chr2-151519013-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 435962.
• BP7: Synonymous conserved (PhyloP=-0.075 with no splicing effect.
• BS2: High Homozygotes in GnomAdExome4 at 2 AD,AR geneVariant has number of homozygotes lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000397345.8. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NEB	NM_001164507.2	MANE Plus Clinical	c.22647G>A	p.Glu7549Glu	synonymous	Exon 155 of 182	NP_001157979.2
	NEB	NM_001164508.2	MANE Select	c.22647G>A	p.Glu7549Glu	synonymous	Exon 155 of 182	NP_001157980.2
	NEB	NM_001271208.2		c.22752G>A	p.Glu7584Glu	synonymous	Exon 156 of 183	NP_001258137.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NEB	ENST00000397345.8	TSL:5 MANE Select	c.22647G>A	p.Glu7549Glu	synonymous	Exon 155 of 182	ENSP00000380505.3
	NEB	ENST00000427231.7	TSL:5 MANE Plus Clinical	c.22647G>A	p.Glu7549Glu	synonymous	Exon 155 of 182	ENSP00000416578.2
	NEB	ENST00000409198.5	TSL:5	c.17544G>A	p.Glu5848Glu	synonymous	Exon 128 of 150	ENSP00000386259.1

Frequencies

GnomAD3 genomes AF: 0.000276 AC: 42 AN: 152202 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000283

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000470

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000478 AC: 119 AN: 248970 AF XY: 0.000555

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000870

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00107

Gnomad NFE exome AF: 0.000815

Gnomad OTH exome AF: 0.000166

GnomAD4 exome AF: 0.000506 AC: 739 AN: 1461420 Hom.: 2 Cov.: 30 AF XY: 0.000470 AC XY: 342 AN XY: 726996

African (AFR) AF: 0.0000299 AC: 1 AN: 33472

American (AMR) AF: 0.000112 AC: 5 AN: 44700

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39674

South Asian (SAS) AF: 0.00 AC: 0 AN: 86238

European-Finnish (FIN) AF: 0.00112 AC: 60 AN: 53394

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.000595 AC: 661 AN: 1111676

Other (OTH) AF: 0.000199 AC: 12 AN: 60368

GnomAD4 genome AF: 0.000276 AC: 42 AN: 152320 Hom.: 0 Cov.: 32 AF XY: 0.000269 AC XY: 20 AN XY: 74482

African (AFR) AF: 0.000120 AC: 5 AN: 41580

American (AMR) AF: 0.000131 AC: 2 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.000283 AC: 3 AN: 10610

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000470 AC: 32 AN: 68026

Other (OTH) AF: 0.00 AC: 0 AN: 2112

Alfa AF: 0.000564 Hom.: 0

Bravo AF: 0.000272

EpiCase AF: 0.000545

EpiControl AF: 0.000652

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	1	Nemaline myopathy 2 (2)
-	-	2	not provided (2)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.30
CADD	Benign	1.3
DANN	Benign	0.74
PhyloP100		-0.075
Mutation Taster		=91/9	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs201688876; hg19: chr2-152375527;