rs1057521205

chr1-237511777-G-Achr1-237511777-G-T

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6 BP7 BS2

The NM_001035.3(RYR2):c.2808G>A(p.Ser936=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000825 in 1,479,066 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. S936S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000021 (0 hom., cov: 29)
  • Exomes 𝑓: 0.000089 (0 hom.)
• Consequence: RYR2 NM_001035.3 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:4
• Conservation: PhyloP100: -5.77

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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.93).
• BP6: Variant 1-237511777-G-A is Benign according to our data. Variant chr1-237511777-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 381914.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Likely_benign=4}.
• BP7: Synonymous conserved (PhyloP=-5.77 with no splicing effect.
• BS2: High AC in GnomAdExome at 6 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RYR2	NM_001035.3	c.2808G>A	p.Ser936=	synonymous_variant	24/105	ENST00000366574.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RYR2	ENST00000366574.7	c.2808G>A	p.Ser936=	synonymous_variant	24/105	1	NM_001035.3	P1
RYR2	ENST00000660292.2	c.2808G>A	p.Ser936=	synonymous_variant	24/106
RYR2	ENST00000659194.3	c.2808G>A	p.Ser936=	synonymous_variant	24/105
RYR2	ENST00000609119.2	c.2808G>A	p.Ser936=	synonymous_variant, NMD_transcript_variant	24/104	5

Frequencies

GnomAD3 genomes AF: 0.0000209 AC: 3 AN: 143254 Hom.: 0 Cov.: 29

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000209

Gnomad SAS AF: 0.000219

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000512

GnomAD3 exomes AF: 0.0000335 AC: 6 AN: 178962 Hom.: 0 AF XY: 0.0000316 AC XY: 3 AN XY: 94906

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000428

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000668

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000891 AC: 119 AN: 1335718 Hom.: 0 Cov.: 30 AF XY: 0.0000824 AC XY: 54 AN XY: 655274

Gnomad4 AFR exome AF: 0.0000314

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000142

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000110

Gnomad4 OTH exome AF: 0.0000740

GnomAD4 genome AF: 0.0000209 AC: 3 AN: 143348 Hom.: 0 Cov.: 29 AF XY: 0.0000292 AC XY: 2 AN XY: 68582

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000210

Gnomad4 SAS AF: 0.000220

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.000506

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Catecholaminergic polymorphic ventricular tachycardia 1 Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 22, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 03, 2024	- -

Arrhythmogenic right ventricular dysplasia 2 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 22, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Nov 24, 2015

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. -

Catecholaminergic polymorphic ventricular tachycardia Benign:1

Likely benign, criteria provided, single submitter

clinical testing

All of Us Research Program, National Institutes of Health

Dec 01, 2023

- -

Cardiomyopathy Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Color Diagnostics, LLC DBA Color Health

Dec 04, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
Cadd	Benign	0.015
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: rs1057521205; hg19: chr1-237675077;