rs79811945

Variant names:

• chr1-237610818-G-A
• rs79811945
• NM_001035.3:c.4740G>A

Your query was ambiguous. Multiple possible variants found:

• chr1-237610818-G-A
• chr1-237610818-G-T
• chr1-237610818-G-C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_001035.3(RYR2):​c.4740G>A​(p.Pro1580Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00174 in 1,611,832 control chromosomes in the GnomAD database, including 56 homozygotes. 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. P1580P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0018 (7 hom., cov: 32)
  • Exomes 𝑓: 0.0017 (49 hom.)
• Consequence: RYR2 NM_001035.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: -1.89
• Publications: 7 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=-0.75).
• BP6: Variant 1-237610818-G-A is Benign according to our data. Variant chr1-237610818-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 43795.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.89 with no splicing effect.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.00179 (273/152232) while in subpopulation EAS AF = 0.041 (212/5176). AF 95% confidence interval is 0.0364. There are 7 homozygotes in GnomAd4. There are 131 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 273 AD gene.

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.4740G>A	p.Pro1580Pro	synonymous	Exon 36 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.4740G>A	p.Pro1580Pro	synonymous	Exon 36 of 105	ENSP00000355533.2	Q92736-1
	RYR2	ENST00000661330.2		c.4740G>A	p.Pro1580Pro	synonymous	Exon 36 of 106	ENSP00000499393.2	A0A590UJF6
	RYR2	ENST00000609119.2	TSL:5	n.4740G>A		non_coding_transcript_exon	Exon 36 of 104	ENSP00000499659.2	A0A590UK06

Frequencies

GnomAD3 genomes AF: 0.00175 AC: 266 AN: 152112 Hom.: 7 Cov.: 32

Gnomad AFR AF: 0.000362

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00151

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.0409

Gnomad SAS AF: 0.000624

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.00287

GnomAD2 exomes AF: 0.00341 AC: 838 AN: 245510 AF XY: 0.00316

Gnomad AFR exome AF: 0.000399

Gnomad AMR exome AF: 0.000117

Gnomad ASJ exome AF: 0.000100

Gnomad EAS exome AF: 0.0422

Gnomad FIN exome AF: 0.000234

Gnomad NFE exome AF: 0.000368

Gnomad OTH exome AF: 0.00117

GnomAD4 exome AF: 0.00173 AC: 2531 AN: 1459600 Hom.: 49 Cov.: 31 AF XY: 0.00173 AC XY: 1256 AN XY: 725892

African (AFR) AF: 0.000179 AC: 6 AN: 33454

American (AMR) AF: 0.0000900 AC: 4 AN: 44434

Ashkenazi Jewish (ASJ) AF: 0.0000767 AC: 2 AN: 26078

East Asian (EAS) AF: 0.0509 AC: 2013 AN: 39576

South Asian (SAS) AF: 0.00117 AC: 100 AN: 85774

European-Finnish (FIN) AF: 0.000263 AC: 14 AN: 53286

Middle Eastern (MID) AF: 0.000722 AC: 4 AN: 5544

European-Non Finnish (NFE) AF: 0.000207 AC: 230 AN: 1111176

Other (OTH) AF: 0.00262 AC: 158 AN: 60278

GnomAD4 genome AF: 0.00179 AC: 273 AN: 152232 Hom.: 7 Cov.: 32 AF XY: 0.00176 AC XY: 131 AN XY: 74438

African (AFR) AF: 0.000530 AC: 22 AN: 41538

American (AMR) AF: 0.00150 AC: 23 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3472

East Asian (EAS) AF: 0.0410 AC: 212 AN: 5176

South Asian (SAS) AF: 0.000625 AC: 3 AN: 4802

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10608

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000882 AC: 6 AN: 68028

Other (OTH) AF: 0.00284 AC: 6 AN: 2114

Alfa AF: 0.00109 Hom.: 2

Bravo AF: 0.00193

Asia WGS AF: 0.0180 AC: 64 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	2	Cardiomyopathy (2)
-	-	2	Catecholaminergic polymorphic ventricular tachycardia 1 (2)
-	-	1	Arrhythmogenic right ventricular dysplasia 2 (1)
-	-	1	Cardiovascular phenotype (1)
-	-	1	Catecholaminergic polymorphic ventricular tachycardia (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.75
CADD	Benign	0.79
DANN	Benign	0.81
PhyloP100		-1.9
Mutation Taster		=89/11	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: rs79811945; hg19: chr1-237774118; COSMIC: COSV63687519;