rs863223355

chr1-237500745-A-Cchr1-237500745-A-G

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP2 PP3 PP5_Moderate

The NM_001035.3(RYR2):c.2238A>C(p.Gln746His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: RYR2 NM_001035.3 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: -0.221

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, RYR2
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.784
• PP5: Variant 1-237500745-A-C is Pathogenic according to our data. Variant chr1-237500745-A-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 208397.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RYR2	NM_001035.3	c.2238A>C	p.Gln746His	missense_variant	21/105	ENST00000366574.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RYR2	ENST00000366574.7	c.2238A>C	p.Gln746His	missense_variant	21/105	1	NM_001035.3	P1
RYR2	ENST00000660292.2	c.2238A>C	p.Gln746His	missense_variant	21/106
RYR2	ENST00000659194.3	c.2238A>C	p.Gln746His	missense_variant	21/105
RYR2	ENST00000609119.2	c.2238A>C	p.Gln746His	missense_variant, NMD_transcript_variant	21/104	5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Childhood-onset schizophrenia Pathogenic:1

Likely pathogenic, criteria provided, single submitter

research

Dr. Guy Rouleau's laboratory, McGill University

Jan 01, 2014

COS with PDD NOS, Asperger's Disorder, Separation Anxiety Disorder -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.37
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Uncertain	0.040
Cadd	Benign	13
Dann	Uncertain	0.98
DEOGEN2	Uncertain	0.75	D;T
Eigen	Benign	-0.42
Eigen_PC	Benign	-0.61
FATHMM_MKL	Benign	0.70	D
LIST_S2	Uncertain	0.92	D;D
M_CAP	Uncertain	0.18	D
MetaRNN	Pathogenic	0.78	D;D
MetaSVM	Uncertain	-0.17	T
MutationAssessor	Uncertain	2.0	M;.
MutationTaster	Benign	0.94	D
PrimateAI	Uncertain	0.72	T
PROVEAN	Uncertain	-3.7	D;.
REVEL	Uncertain	0.52
Sift	Benign	0.13	T;.
Polyphen		1.0	D;.
Vest4		0.53
MutPred		0.71		Gain of catalytic residue at L748 (P = 0.0989);.;
MVP		0.87
MPC		0.96
ClinPred		0.97	D
GERP RS		-6.0
Varity_R		0.31
gMVP		0.65

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

Publications

LitVar

Other links and lift over

dbSNP: rs863223355; hg19: chr1-237664045;