1-237614100-C-T

Variant names:

• chr1-237614100-C-T
• rs767540663
• NM_001035.3:c.4972C>T

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 3P and 4B. PP2 PP3_Moderate BS2

The NM_001035.3(RYR2):​c.4972C>T​(p.Leu1658Phe) variant causes a missense change. The variant allele was found at a frequency of 0.00000753 in 1,461,698 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L1658V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000075 (0 hom.)
• Consequence: RYR2 NM_001035.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 6.12
• 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: Likely_benign. The variant received -1 ACMG points.

• 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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.894
• BS2: High AC in GnomAdExome4 at 11 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.4972C>T	p.Leu1658Phe	missense	Exon 37 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.4972C>T	p.Leu1658Phe	missense	Exon 37 of 105	ENSP00000355533.2	Q92736-1
	RYR2	ENST00000661330.2		c.4972C>T	p.Leu1658Phe	missense	Exon 37 of 106	ENSP00000499393.2	A0A590UJF6
	RYR2	ENST00000609119.2	TSL:5	n.4972C>T		non_coding_transcript_exon	Exon 37 of 104	ENSP00000499659.2	A0A590UK06

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.0000161 AC: 4 AN: 248778 AF XY: 0.0000148

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000355

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000753 AC: 11 AN: 1461698 Hom.: 0 Cov.: 31 AF XY: 0.00000550 AC XY: 4 AN XY: 727128

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53402

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000899 AC: 10 AN: 1111864

Other (OTH) AF: 0.0000166 AC: 1 AN: 60372

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000704 Hom.: 0

ExAC AF: 0.0000331 AC: 4

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	2	-	Catecholaminergic polymorphic ventricular tachycardia (2)
-	1	-	Catecholaminergic polymorphic ventricular tachycardia 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.78
BayesDel_addAF	Pathogenic	0.30	D
BayesDel_noAF	Pathogenic	0.29
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.92	D
Eigen	Pathogenic	0.81
Eigen_PC	Pathogenic	0.73
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.88	D
MetaRNN	Pathogenic	0.89	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.7	M
PhyloP100		6.1
PrimateAI	Uncertain	0.79	T
PROVEAN	Uncertain	-3.4	D
REVEL	Pathogenic	0.81
Sift	Uncertain	0.0010	D
Polyphen		1.0	D
Vest4		0.75
MutPred		0.55		Gain of methylation at R1659 (P = 0.0988)
MVP		0.85
MPC		1.2
ClinPred		0.94	D
GERP RS		5.6
Varity_R		0.63
gMVP		0.57
Mutation Taster		=11/89	disease causing

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: rs767540663; hg19: chr1-237777400;