rs2306238

chr1-237550803-G-A

Variant summary

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

The NM_001035.3(RYR2):c.3214+112G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.208 in 1,178,198 control chromosomes in the GnomAD database, including 26,982 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.19 (2961 hom., cov: 32)
  • Exomes 𝑓: 0.21 (24021 hom.)
• Consequence: RYR2 NM_001035.3 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.386

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]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 1-237550803-G-A is Benign according to our data. Variant chr1-237550803-G-A is described in ClinVar as [Benign]. Clinvar id is 672392.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.274 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RYR2	NM_001035.3	c.3214+112G>A		intron_variant		ENST00000366574.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RYR2	ENST00000366574.7	c.3214+112G>A		intron_variant		1	NM_001035.3	P1
RYR2	ENST00000659194.3	c.3214+112G>A		intron_variant
RYR2	ENST00000660292.2	c.3214+112G>A		intron_variant
RYR2	ENST00000609119.2	c.3214+112G>A		intron_variant, NMD_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.186 AC: 28310 AN: 152024 Hom.: 2956 Cov.: 32

Gnomad AFR AF: 0.0807

Gnomad AMI AF: 0.231

Gnomad AMR AF: 0.281

Gnomad ASJ AF: 0.263

Gnomad EAS AF: 0.256

Gnomad SAS AF: 0.285

Gnomad FIN AF: 0.186

Gnomad MID AF: 0.226

Gnomad NFE AF: 0.211

Gnomad OTH AF: 0.232

GnomAD4 exome AF: 0.211 AC: 216535 AN: 1026054 Hom.: 24021 AF XY: 0.214 AC XY: 107224 AN XY: 502146

Gnomad4 AFR exome AF: 0.0698

Gnomad4 AMR exome AF: 0.302

Gnomad4 ASJ exome AF: 0.252

Gnomad4 EAS exome AF: 0.289

Gnomad4 SAS exome AF: 0.265

Gnomad4 FIN exome AF: 0.179

Gnomad4 NFE exome AF: 0.208

Gnomad4 OTH exome AF: 0.215

GnomAD4 genome AF: 0.186 AC: 28322 AN: 152144 Hom.: 2961 Cov.: 32 AF XY: 0.190 AC XY: 14129 AN XY: 74366

Gnomad4 AFR AF: 0.0805

Gnomad4 AMR AF: 0.281

Gnomad4 ASJ AF: 0.263

Gnomad4 EAS AF: 0.256

Gnomad4 SAS AF: 0.287

Gnomad4 FIN AF: 0.186

Gnomad4 NFE AF: 0.211

Gnomad4 OTH AF: 0.230

Alfa AF: 0.214 Hom.: 4883

Bravo AF: 0.191

Asia WGS AF: 0.244 AC: 851 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 15, 2018

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
Cadd	Benign	0.96
Dann	Benign	0.65

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: rs2306238; hg19: chr1-237714103; COSMIC: COSV63672640; COSMIC: COSV63672640;