1-237727137-C-T

Variant names:

• chr1-237727137-C-T
• rs2685301
• NM_001035.3:c.10776C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001035.3(RYR2):​c.10776C>T​(p.Ser3592Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.993 in 1,606,748 control chromosomes in the GnomAD database, including 792,480 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.96 (70779 hom., cov: 31)
  • Exomes 𝑓: 1.0 (721701 hom.)
• Consequence: RYR2 NM_001035.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:17
• Conservation: PhyloP100: -3.73
• Publications: 19 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: ClinGen, G2P, Orphanet
• catecholaminergic polymorphic ventricular tachycardia 1

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

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen
• 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 1-237727137-C-T is Benign according to our data. Variant chr1-237727137-C-T is described in ClinVar as Benign. ClinVar VariationId is 43702.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-3.73 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.993 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001035.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RYR2	NM_001035.3	MANE Select	c.10776C>T	p.Ser3592Ser	synonymous	Exon 76 of 105	NP_001026.2	Q92736-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RYR2	ENST00000366574.7	TSL:1 MANE Select	c.10776C>T	p.Ser3592Ser	synonymous	Exon 76 of 105	ENSP00000355533.2	Q92736-1
	RYR2	ENST00000661330.2		c.10776C>T	p.Ser3592Ser	synonymous	Exon 76 of 106	ENSP00000499393.2	A0A590UJF6
	RYR2	ENST00000609119.2	TSL:5	n.*1811C>T		non_coding_transcript_exon	Exon 74 of 104	ENSP00000499659.2	A0A590UK06

Frequencies

GnomAD3 genomes AF: 0.963 AC: 146411 AN: 152066 Hom.: 70732 Cov.: 31

Gnomad AFR AF: 0.870

Gnomad AMI AF: 0.999

Gnomad AMR AF: 0.987

Gnomad ASJ AF: 1.00

Gnomad EAS AF: 1.00

Gnomad SAS AF: 0.999

Gnomad FIN AF: 1.00

Gnomad MID AF: 0.994

Gnomad NFE AF: 0.999

Gnomad OTH AF: 0.977

GnomAD2 exomes AF: 0.991 AC: 245348 AN: 247674 AF XY: 0.993

Gnomad AFR exome AF: 0.868

Gnomad AMR exome AF: 0.995

Gnomad ASJ exome AF: 1.00

Gnomad EAS exome AF: 1.00

Gnomad FIN exome AF: 1.00

Gnomad NFE exome AF: 0.999

Gnomad OTH exome AF: 0.994

GnomAD4 exome AF: 0.996 AC: 1448658 AN: 1454564 Hom.: 721701 Cov.: 30 AF XY: 0.996 AC XY: 721328 AN XY: 723880

African (AFR) AF: 0.865 AC: 28769 AN: 33266

American (AMR) AF: 0.994 AC: 44211 AN: 44490

Ashkenazi Jewish (ASJ) AF: 1.00 AC: 25948 AN: 25950

East Asian (EAS) AF: 1.00 AC: 39574 AN: 39574

South Asian (SAS) AF: 0.999 AC: 85637 AN: 85706

European-Finnish (FIN) AF: 1.00 AC: 53301 AN: 53302

Middle Eastern (MID) AF: 0.992 AC: 5704 AN: 5750

European-Non Finnish (NFE) AF: 1.00 AC: 1106051 AN: 1106500

Other (OTH) AF: 0.991 AC: 59463 AN: 60026

GnomAD4 genome AF: 0.963 AC: 146517 AN: 152184 Hom.: 70779 Cov.: 31 AF XY: 0.965 AC XY: 71785 AN XY: 74392

African (AFR) AF: 0.871 AC: 36130 AN: 41502

American (AMR) AF: 0.987 AC: 15065 AN: 15270

Ashkenazi Jewish (ASJ) AF: 1.00 AC: 3472 AN: 3472

East Asian (EAS) AF: 1.00 AC: 5178 AN: 5178

South Asian (SAS) AF: 0.999 AC: 4815 AN: 4820

European-Finnish (FIN) AF: 1.00 AC: 10628 AN: 10628

Middle Eastern (MID) AF: 0.993 AC: 292 AN: 294

European-Non Finnish (NFE) AF: 0.999 AC: 67963 AN: 67998

Other (OTH) AF: 0.978 AC: 2063 AN: 2110

Alfa AF: 0.977 Hom.: 74820

Bravo AF: 0.957

Asia WGS AF: 0.994 AC: 3457 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not specified (6)
-	-	3	Catecholaminergic polymorphic ventricular tachycardia 1 (3)
-	-	2	Arrhythmogenic right ventricular dysplasia 2 (2)
-	-	2	not provided (2)
-	-	1	Cardiac arrhythmia (1)
-	-	1	Cardiomyopathy (1)
-	-	1	Cardiovascular phenotype (1)
-	-	1	Catecholaminergic polymorphic ventricular tachycardia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.0070
DANN	Benign	0.36
PhyloP100		-3.7
Mutation Taster		=89/11	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.10		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: rs2685301; hg19: chr1-237890437; COSMIC: COSV108198698;