NM_001035.3:c.9963G>A

Variant names:

• chr1-237708919-G-A
• rs199730192
• NM_001035.3:c.9963G>A

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BS1 BS2

The NM_001035.3(RYR2):​c.9963G>A​(p.Pro3321Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000265 in 1,611,798 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00012 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00028 (1 hom.)
• Consequence: RYR2 NM_001035.3 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:10
• Conservation: PhyloP100: -0.224
• Publications: 1 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 1-237708919-G-A is Benign according to our data. Variant chr1-237708919-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 412820.
• BP7: Synonymous conserved (PhyloP=-0.224 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000125 (19/152022) while in subpopulation NFE AF = 0.000265 (18/68026). AF 95% confidence interval is 0.000171. There are 0 homozygotes in GnomAd4. There are 10 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 19 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.9963G>A	p.Pro3321Pro	synonymous	Exon 69 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.9963G>A	p.Pro3321Pro	synonymous	Exon 69 of 105	ENSP00000355533.2	Q92736-1
	RYR2	ENST00000661330.2		c.9963G>A	p.Pro3321Pro	synonymous	Exon 69 of 106	ENSP00000499393.2	A0A590UJF6
	RYR2	ENST00000609119.2	TSL:5	n.*998G>A		non_coding_transcript_exon	Exon 67 of 104	ENSP00000499659.2	A0A590UK06

Frequencies

GnomAD3 genomes AF: 0.000125 AC: 19 AN: 152022 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000265

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000138 AC: 34 AN: 246802 AF XY: 0.000119

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000876

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000112

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000251

Gnomad OTH exome AF: 0.000167

GnomAD4 exome AF: 0.000279 AC: 408 AN: 1459776 Hom.: 1 Cov.: 30 AF XY: 0.000264 AC XY: 192 AN XY: 726126

African (AFR) AF: 0.00 AC: 0 AN: 33450

American (AMR) AF: 0.0000897 AC: 4 AN: 44580

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26104

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39674

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86118

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53342

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.000358 AC: 398 AN: 1110448

Other (OTH) AF: 0.0000663 AC: 4 AN: 60296

GnomAD4 genome AF: 0.000125 AC: 19 AN: 152022 Hom.: 0 Cov.: 32 AF XY: 0.000135 AC XY: 10 AN XY: 74252

African (AFR) AF: 0.00 AC: 0 AN: 41366

American (AMR) AF: 0.00 AC: 0 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10578

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000265 AC: 18 AN: 68026

Other (OTH) AF: 0.00 AC: 0 AN: 2088

Alfa AF: 0.000240 Hom.: 0

Bravo AF: 0.000121

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	2	Catecholaminergic polymorphic ventricular tachycardia 1 (2)
-	1	-	Arrhythmogenic right ventricular dysplasia 2 (1)
-	-	1	Cardiomyopathy (1)
-	-	1	Cardiovascular phenotype (1)
-	-	1	Catecholaminergic polymorphic ventricular tachycardia (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	5.6
DANN	Benign	0.46
PhyloP100		-0.22
PromoterAI		0.0058	Neutral
Mutation Taster		=98/2	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: rs199730192; hg19: chr1-237872219; COSMIC: COSV63680489;