rs4427395

chr1-237699287-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.9128+262G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.536 in 151,962 control chromosomes in the GnomAD database, including 25,669 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.54 (25669 hom., cov: 32)
• Consequence: RYR2 NM_001035.3 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.186

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=-0.89).
• BP6: Variant 1-237699287-G-A is Benign according to our data. Variant chr1-237699287-G-A is described in ClinVar as [Benign]. Clinvar id is 683792.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.696 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RYR2	NM_001035.3	c.9128+262G>A		intron_variant		ENST00000366574.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RYR2	ENST00000366574.7	c.9128+262G>A		intron_variant		1	NM_001035.3	P1
RYR2	ENST00000659194.3	c.9128+262G>A		intron_variant
RYR2	ENST00000660292.2	c.9128+262G>A		intron_variant
RYR2	ENST00000609119.2	c.*163+262G>A		intron_variant, NMD_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.537 AC: 81489 AN: 151846 Hom.: 25677 Cov.: 32

Gnomad AFR AF: 0.194

Gnomad AMI AF: 0.605

Gnomad AMR AF: 0.606

Gnomad ASJ AF: 0.649

Gnomad EAS AF: 0.392

Gnomad SAS AF: 0.651

Gnomad FIN AF: 0.686

Gnomad MID AF: 0.723

Gnomad NFE AF: 0.701

Gnomad OTH AF: 0.566

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.536 AC: 81475 AN: 151962 Hom.: 25669 Cov.: 32 AF XY: 0.539 AC XY: 40057 AN XY: 74268

Gnomad4 AFR AF: 0.193

Gnomad4 AMR AF: 0.605

Gnomad4 ASJ AF: 0.649

Gnomad4 EAS AF: 0.391

Gnomad4 SAS AF: 0.651

Gnomad4 FIN AF: 0.686

Gnomad4 NFE AF: 0.701

Gnomad4 OTH AF: 0.567

Alfa AF: 0.670 Hom.: 49798

Bravo AF: 0.511

Asia WGS AF: 0.519 AC: 1802 AN: 3476

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 18, 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	-0.89
Cadd	Benign	1.5
Dann	Benign	0.52

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: rs4427395; hg19: chr1-237862587;