rs2779430

Variant names:

• chr1-237591903-T-C
• rs2779430
• NM_001035.3:c.4275+50T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001035.3(RYR2):​c.4275+50T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.463 in 1,306,238 control chromosomes in the GnomAD database, including 143,814 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.40 (13463 hom., cov: 31)
  • Exomes 𝑓: 0.47 (130351 hom.)
• Consequence: RYR2 NM_001035.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.610
• Publications: 8 publications found

Genes affected

RYR2 (HGNC:10484): (ryanodine receptor 2) This gene encodes a ryanodine receptor found in cardiac muscle sarcoplasmic reticulum. The encoded protein is one of the components of a calcium channel, composed of a tetramer of the ryanodine receptor proteins and a tetramer of FK506 binding protein 1B proteins, that supplies calcium to cardiac muscle. Mutations in this gene are associated with stress-induced polymorphic ventricular tachycardia and arrhythmogenic right ventricular dysplasia. [provided by RefSeq, Jul 2008]

RYR2 Gene-Disease associations (from GenCC):

• arrhythmogenic right ventricular dysplasia 2

  Inheritance: AD Classification: DEFINITIVE, NO_KNOWN Submitted by: Laboratory for Molecular Medicine, Ambry Genetics
• catecholaminergic polymorphic ventricular tachycardia

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen, G2P
• catecholaminergic polymorphic ventricular tachycardia 1

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• hypertrophic cardiomyopathy

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen
• arrhythmogenic right ventricular cardiomyopathy

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 1-237591903-T-C is Benign according to our data. Variant chr1-237591903-T-C is described in ClinVar as Benign. ClinVar VariationId is 257212.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.494 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RYR2	NM_001035.3	c.4275+50T>C		intron_variant	Intron 32 of 104	ENST00000366574.7	NP_001026.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RYR2	ENST00000366574.7	c.4275+50T>C		intron_variant	Intron 32 of 104	1	NM_001035.3	ENSP00000355533.2
RYR2	ENST00000661330.2	c.4275+50T>C		intron_variant	Intron 32 of 105			ENSP00000499393.2
RYR2	ENST00000609119.2	n.4275+50T>C		intron_variant	Intron 32 of 103	5		ENSP00000499659.2

Frequencies

GnomAD3 genomes AF: 0.398 AC: 60392 AN: 151916 Hom.: 13459 Cov.: 31

Gnomad AFR AF: 0.197

Gnomad AMI AF: 0.460

Gnomad AMR AF: 0.503

Gnomad ASJ AF: 0.471

Gnomad EAS AF: 0.324

Gnomad SAS AF: 0.329

Gnomad FIN AF: 0.501

Gnomad MID AF: 0.396

Gnomad NFE AF: 0.485

Gnomad OTH AF: 0.424

GnomAD2 exomes AF: 0.455 AC: 82759 AN: 181900 AF XY: 0.450

Gnomad AFR exome AF: 0.191

Gnomad AMR exome AF: 0.605

Gnomad ASJ exome AF: 0.476

Gnomad EAS exome AF: 0.310

Gnomad FIN exome AF: 0.509

Gnomad NFE exome AF: 0.482

Gnomad OTH exome AF: 0.478

GnomAD4 exome AF: 0.472 AC: 544634 AN: 1154204 Hom.: 130351 Cov.: 15 AF XY: 0.468 AC XY: 272265 AN XY: 581534

African (AFR) AF: 0.181 AC: 4881 AN: 27024

American (AMR) AF: 0.598 AC: 21879 AN: 36600

Ashkenazi Jewish (ASJ) AF: 0.478 AC: 11117 AN: 23236

East Asian (EAS) AF: 0.354 AC: 12914 AN: 36444

South Asian (SAS) AF: 0.345 AC: 25693 AN: 74386

European-Finnish (FIN) AF: 0.506 AC: 25526 AN: 50490

Middle Eastern (MID) AF: 0.404 AC: 2085 AN: 5164

European-Non Finnish (NFE) AF: 0.491 AC: 418053 AN: 850810

Other (OTH) AF: 0.449 AC: 22486 AN: 50050

GnomAD4 genome AF: 0.397 AC: 60397 AN: 152034 Hom.: 13463 Cov.: 31 AF XY: 0.399 AC XY: 29617 AN XY: 74304

African (AFR) AF: 0.196 AC: 8152 AN: 41494

American (AMR) AF: 0.504 AC: 7694 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.471 AC: 1632 AN: 3466

East Asian (EAS) AF: 0.324 AC: 1669 AN: 5150

South Asian (SAS) AF: 0.330 AC: 1588 AN: 4812

European-Finnish (FIN) AF: 0.501 AC: 5283 AN: 10550

Middle Eastern (MID) AF: 0.381 AC: 112 AN: 294

European-Non Finnish (NFE) AF: 0.485 AC: 32962 AN: 67962

Other (OTH) AF: 0.419 AC: 886 AN: 2116

Alfa AF: 0.448 Hom.: 6445

Bravo AF: 0.395

Asia WGS AF: 0.317 AC: 1103 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 15, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	1.8
DANN	Benign	0.41
PhyloP100		-0.61
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2779430; hg19: chr1-237755203; COSMIC: COSV63689427;