1-237718470-C-T

Variant names:

• chr1-237718470-C-T
• rs2797441
• NM_001035.3:c.10503C>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.10503C>T​(p.Thr3501Thr) 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 1,573,354 control chromosomes in the GnomAD database, including 775,840 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. T3501T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.96 (70832 hom., cov: 33)
  • Exomes 𝑓: 1.0 (705008 hom.)
• Consequence: RYR2 NM_001035.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:18
• Conservation: PhyloP100: -0.622
• Publications: 18 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.59).
• BP6: Variant 1-237718470-C-T is Benign according to our data. Variant chr1-237718470-C-T is described in ClinVar as Benign. ClinVar VariationId is 43699.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.622 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RYR2	NM_001035.3	MANE Select	c.10503C>T	p.Thr3501Thr	synonymous	Exon 73 of 105	NP_001026.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RYR2	ENST00000366574.7	TSL:1 MANE Select	c.10503C>T	p.Thr3501Thr	synonymous	Exon 73 of 105	ENSP00000355533.2
	RYR2	ENST00000661330.2		c.10503C>T	p.Thr3501Thr	synonymous	Exon 73 of 106	ENSP00000499393.2
	RYR2	ENST00000609119.2	TSL:5	n.*1538C>T		non_coding_transcript_exon	Exon 71 of 104	ENSP00000499659.2

Frequencies

GnomAD3 genomes AF: 0.963 AC: 146520 AN: 152190 Hom.: 70782 Cov.: 33

Gnomad AFR AF: 0.870

Gnomad AMI AF: 0.999

Gnomad AMR AF: 0.986

Gnomad ASJ AF: 1.00

Gnomad EAS AF: 1.00

Gnomad SAS AF: 0.999

Gnomad FIN AF: 1.00

Gnomad MID AF: 0.997

Gnomad NFE AF: 0.999

Gnomad OTH AF: 0.977

GnomAD2 exomes AF: 0.991 AC: 244166 AN: 246488 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: 1415204 AN: 1421046 Hom.: 705008 Cov.: 23 AF XY: 0.996 AC XY: 706557 AN XY: 709080

African (AFR) AF: 0.864 AC: 28226 AN: 32674

American (AMR) AF: 0.994 AC: 43885 AN: 44162

Ashkenazi Jewish (ASJ) AF: 1.00 AC: 25722 AN: 25724

East Asian (EAS) AF: 1.00 AC: 39334 AN: 39334

South Asian (SAS) AF: 0.999 AC: 83929 AN: 83998

European-Finnish (FIN) AF: 1.00 AC: 53119 AN: 53120

Middle Eastern (MID) AF: 0.992 AC: 5655 AN: 5700

European-Non Finnish (NFE) AF: 1.00 AC: 1076949 AN: 1077390

Other (OTH) AF: 0.991 AC: 58385 AN: 58944

GnomAD4 genome AF: 0.963 AC: 146629 AN: 152308 Hom.: 70832 Cov.: 33 AF XY: 0.965 AC XY: 71863 AN XY: 74474

African (AFR) AF: 0.870 AC: 36155 AN: 41536

American (AMR) AF: 0.986 AC: 15093 AN: 15300

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

East Asian (EAS) AF: 1.00 AC: 5186 AN: 5186

South Asian (SAS) AF: 0.999 AC: 4823 AN: 4828

European-Finnish (FIN) AF: 1.00 AC: 10626 AN: 10626

Middle Eastern (MID) AF: 0.997 AC: 293 AN: 294

European-Non Finnish (NFE) AF: 0.999 AC: 68002 AN: 68038

Other (OTH) AF: 0.977 AC: 2068 AN: 2116

Alfa AF: 0.979 Hom.: 140469

Bravo AF: 0.957

Asia WGS AF: 0.994 AC: 3452 AN: 3474

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	7	not specified (7)
-	-	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	-0.59
CADD	Benign	0.14
DANN	Benign	0.57
PhyloP100		-0.62
Mutation Taster		=90/10	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs2797441; hg19: chr1-237881770; COSMIC: COSV108198697; COSMIC: COSV108198697;