NM_001035.3:c.2808G>T

Variant names:

• chr1-237511777-G-T
• rs1057521205
• NM_001035.3:c.2808G>T

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 2P and 13B. PM2 BP4_Strong BP6_Very_Strong BP7

The NM_001035.3(RYR2):​c.2808G>T​(p.Ser936Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000749 in 1,335,720 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 Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. S936S) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 29)
  • Exomes 𝑓: 7.5e-7 (0 hom.)
• Consequence: RYR2 NM_001035.3 synonymous
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -5.77
• Publications: 0 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 -11 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.98).
• BP6: Variant 1-237511777-G-T is Benign according to our data. Variant chr1-237511777-G-T is described in ClinVar as Likely_benign. ClinVar VariationId is 463589.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-5.77 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RYR2	NM_001035.3	c.2808G>T	p.Ser936Ser	synonymous_variant	Exon 24 of 105	ENST00000366574.7	NP_001026.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RYR2	ENST00000366574.7	c.2808G>T	p.Ser936Ser	synonymous_variant	Exon 24 of 105	1	NM_001035.3	ENSP00000355533.2
RYR2	ENST00000661330.2	c.2808G>T	p.Ser936Ser	synonymous_variant	Exon 24 of 106			ENSP00000499393.2
RYR2	ENST00000609119.2	n.2808G>T		non_coding_transcript_exon_variant	Exon 24 of 104	5		ENSP00000499659.2

Frequencies

GnomAD3 genomes Cov.: 29

GnomAD4 exome AF: 7.49e-7 AC: 1 AN: 1335720 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 655274

African (AFR) AF: 0.00 AC: 0 AN: 31874

American (AMR) AF: 0.00 AC: 0 AN: 37150

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23082

East Asian (EAS) AF: 0.00 AC: 0 AN: 35894

South Asian (SAS) AF: 0.00 AC: 0 AN: 70220

European-Finnish (FIN) AF: 0.0000212 AC: 1 AN: 47090

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5280

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1031066

Other (OTH) AF: 0.00 AC: 0 AN: 54064

GnomAD4 genome Cov.: 29

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Catecholaminergic polymorphic ventricular tachycardia Benign:1

Sep 17, 2023

All of Us Research Program, National Institutes of Health

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Cardiomyopathy Benign:1

Nov 06, 2022

Color Diagnostics, LLC DBA Color Health

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Catecholaminergic polymorphic ventricular tachycardia 1 Benign:1

May 26, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Cardiovascular phenotype Benign:1

Jun 16, 2021

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.98
CADD	Benign	0.0040
DANN	Benign	0.45
PhyloP100		-5.8
Mutation Taster		=90/10	polymorphism

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: rs1057521205; hg19: chr1-237675077;