chr1-237042557-G-T

Variant names:

• chr1-237042557-G-T
• rs746811389
• NM_001035.3:c.36G>T

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM1 PM2 PP2

The NM_001035.3(RYR2):​c.36G>T​(p.Gln12His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000027 in 1,109,710 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Synonymous variant affecting the same amino acid position (i.e. Q12Q) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: RYR2 NM_001035.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.650
• 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 5 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 17 uncertain in NM_001035.3
• 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.

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.36G>T	p.Gln12His	missense	Exon 1 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.36G>T	p.Gln12His	missense	Exon 1 of 105	ENSP00000355533.2
	RYR2	ENST00000661330.2		c.36G>T	p.Gln12His	missense	Exon 1 of 106	ENSP00000499393.2
	RYR2	ENST00000609119.2	TSL:5	n.36G>T		non_coding_transcript_exon	Exon 1 of 104	ENSP00000499659.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000270 AC: 3 AN: 1109710 Hom.: 0 Cov.: 31 AF XY: 0.00000190 AC XY: 1 AN XY: 525762

African (AFR) AF: 0.00 AC: 0 AN: 23608

American (AMR) AF: 0.00 AC: 0 AN: 9732

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 14506

East Asian (EAS) AF: 0.00 AC: 0 AN: 27476

South Asian (SAS) AF: 0.00 AC: 0 AN: 20430

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 37062

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4566

European-Non Finnish (NFE) AF: 0.00000323 AC: 3 AN: 927776

Other (OTH) AF: 0.00 AC: 0 AN: 44554

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.69
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Uncertain	-0.030
CADD	Benign	22
DANN	Uncertain	0.98
DEOGEN2	Pathogenic	0.84	D
Eigen	Benign	0.18
Eigen_PC	Benign	0.13
FATHMM_MKL	Benign	0.65	D
LIST_S2	Uncertain	0.91	D
M_CAP	Pathogenic	0.98	D
MetaRNN	Uncertain	0.69	D
MetaSVM	Pathogenic	0.85	D
MutationAssessor	Benign	1.7	L
PhyloP100		0.65
PrimateAI	Uncertain	0.79	T
PROVEAN	Benign	-2.2	N
REVEL	Pathogenic	0.76
Sift	Uncertain	0.017	D
Polyphen		0.98	D
Vest4		0.35
MutPred		0.56		Gain of sheet (P = 0.039)
MVP		0.82
MPC		0.70
ClinPred		0.68	D
GERP RS		2.3
PromoterAI		0.065	Neutral
Varity_R		0.35
gMVP		0.21
Mutation Taster		=59/41	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: rs746811389; hg19: chr1-237205857; COSMIC: COSV99053485;