1-237651484-G-T

Variant names:

• chr1-237651484-G-T
• rs59331340
• NM_001035.3:c.7807G>T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_001035.3(RYR2):​c.7807G>T​(p.Ala2603Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000708 in 1,413,350 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A2603G) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
• Consequence: RYR2 NM_001035.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.62
• Publications: 0 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: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the RYR2 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 195 curated pathogenic missense variants (we use a threshold of 10). The gene has 55 curated benign missense variants. Gene score misZ: 5.7809 (above the threshold of 3.09). Trascript score misZ: 6.4158 (above the threshold of 3.09). GenCC associations: The gene is linked to hypertrophic cardiomyopathy, catecholaminergic polymorphic ventricular tachycardia 1, catecholaminergic polymorphic ventricular tachycardia, arrhythmogenic right ventricular dysplasia 2, arrhythmogenic right ventricular cardiomyopathy.
• BP4: Computational evidence support a benign effect (MetaRNN=0.2009657).

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.7807G>T	p.Ala2603Ser	missense	Exon 51 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.7807G>T	p.Ala2603Ser	missense	Exon 51 of 105	ENSP00000355533.2
	RYR2	ENST00000661330.2		c.7807G>T	p.Ala2603Ser	missense	Exon 51 of 106	ENSP00000499393.2
	RYR2	ENST00000609119.2	TSL:5	n.7807G>T		non_coding_transcript_exon	Exon 51 of 104	ENSP00000499659.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.08e-7 AC: 1 AN: 1413350 Hom.: 0 Cov.: 26 AF XY: 0.00000143 AC XY: 1 AN XY: 700480

African (AFR) AF: 0.00 AC: 0 AN: 32480

American (AMR) AF: 0.00 AC: 0 AN: 39358

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25368

East Asian (EAS) AF: 0.00 AC: 0 AN: 38110

South Asian (SAS) AF: 0.0000124 AC: 1 AN: 80544

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51526

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5698

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1081542

Other (OTH) AF: 0.00 AC: 0 AN: 58724

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Uncertain	0.038	T
BayesDel_noAF	Benign	-0.18
CADD	Benign	16
DANN	Benign	0.85
DEOGEN2	Benign	0.40	T
Eigen	Benign	-0.21
Eigen_PC	Benign	-0.020
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Uncertain	0.86	D
M_CAP	Uncertain	0.15	D
MetaRNN	Benign	0.20	T
MetaSVM	Uncertain	0.032	D
MutationAssessor	Benign	0.48	N
PhyloP100		1.6
PrimateAI	Uncertain	0.69	T
PROVEAN	Benign	-0.89	N
REVEL	Uncertain	0.31
Sift	Benign	0.64	T
Polyphen		0.34	B
Vest4		0.16
MutPred		0.35		Gain of disorder (P = 0.0249)
MVP		0.68
MPC		0.35
ClinPred		0.30	T
GERP RS		4.3
PromoterAI		-0.020	Neutral
Varity_R		0.11
gMVP		0.19
Mutation Taster		=63/37	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs59331340; hg19: chr1-237814784;