chr1-237700418-T-G

Variant names:

• chr1-237700418-T-G
• rs2797436
• NM_001035.3:c.9318T>G

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.9318T>G​(p.Ser3106Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.994 in 1,609,324 control chromosomes in the GnomAD database, including 796,067 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. S3106S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.97 (71957 hom., cov: 30)
  • Exomes 𝑓: 1.0 (724110 hom.)
• Consequence: RYR2 NM_001035.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:18
• Conservation: PhyloP100: -4.04
• Publications: 21 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=-0.88).
• BP6: Variant 1-237700418-T-G is Benign according to our data. Variant chr1-237700418-T-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 43836.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-4.04 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.9318T>G	p.Ser3106Ser	synonymous	Exon 65 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.9318T>G	p.Ser3106Ser	synonymous	Exon 65 of 105	ENSP00000355533.2	Q92736-1
	RYR2	ENST00000661330.2		c.9318T>G	p.Ser3106Ser	synonymous	Exon 65 of 106	ENSP00000499393.2	A0A590UJF6
	RYR2	ENST00000609119.2	TSL:5	n.*353T>G		non_coding_transcript_exon	Exon 63 of 104	ENSP00000499659.2	A0A590UK06

Frequencies

GnomAD3 genomes AF: 0.972 AC: 147706 AN: 152006 Hom.: 71905 Cov.: 30

Gnomad AFR AF: 0.902

Gnomad AMI AF: 0.999

Gnomad AMR AF: 0.989

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: 0.981

GnomAD2 exomes AF: 0.993 AC: 242629 AN: 244388 AF XY: 0.994

Gnomad AFR exome AF: 0.901

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: 0.995

GnomAD4 exome AF: 0.997 AC: 1452537 AN: 1457202 Hom.: 724110 Cov.: 34 AF XY: 0.997 AC XY: 722685 AN XY: 724682

African (AFR) AF: 0.897 AC: 29947 AN: 33372

American (AMR) AF: 0.994 AC: 44042 AN: 44292

Ashkenazi Jewish (ASJ) AF: 1.00 AC: 26029 AN: 26030

East Asian (EAS) AF: 1.00 AC: 39666 AN: 39668

South Asian (SAS) AF: 0.999 AC: 85321 AN: 85386

European-Finnish (FIN) AF: 1.00 AC: 53227 AN: 53228

Middle Eastern (MID) AF: 0.993 AC: 5723 AN: 5764

European-Non Finnish (NFE) AF: 1.00 AC: 1108819 AN: 1109232

Other (OTH) AF: 0.992 AC: 59763 AN: 60230

GnomAD4 genome AF: 0.972 AC: 147816 AN: 152122 Hom.: 71957 Cov.: 30 AF XY: 0.973 AC XY: 72370 AN XY: 74360

African (AFR) AF: 0.902 AC: 37408 AN: 41458

American (AMR) AF: 0.989 AC: 15126 AN: 15298

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

East Asian (EAS) AF: 1.00 AC: 5162 AN: 5162

South Asian (SAS) AF: 0.999 AC: 4808 AN: 4814

European-Finnish (FIN) AF: 1.00 AC: 10586 AN: 10586

Middle Eastern (MID) AF: 0.997 AC: 291 AN: 292

European-Non Finnish (NFE) AF: 0.999 AC: 67981 AN: 68018

Other (OTH) AF: 0.982 AC: 2071 AN: 2110

Alfa AF: 0.988 Hom.: 41861

Bravo AF: 0.967

Asia WGS AF: 0.995 AC: 3459 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely 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)
-	-	1	Catecholaminergic polymorphic ventricular tachycardia 1;C1832931:Arrhythmogenic right ventricular dysplasia 2;C5542154:Ventricular arrhythmias due to cardiac ryanodine receptor calcium release deficiency syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.0070
DANN	Benign	0.52
PhyloP100		-4.0
Mutation Taster		=88/12	polymorphism (auto)

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: rs2797436; hg19: chr1-237863718; COSMIC: COSV108198696;