rs397516551

Variant names:

• chr1-237660937-A-C
• rs397516551
• NM_001035.3:c.8426A>C

Your query was ambiguous. Multiple possible variants found:

• chr1-237660937-A-C
• chr1-237660937-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP2 PP3

The NM_001035.3(RYR2):​c.8426A>C​(p.Gln2809Pro) variant causes a missense change. 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 Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q2809E) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: RYR2 NM_001035.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.58

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 Uncertain_significance. Variant got 4 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, arrhythmogenic right ventricular cardiomyopathy, catecholaminergic polymorphic ventricular tachycardia 1, arrhythmogenic right ventricular dysplasia 2, catecholaminergic polymorphic ventricular tachycardia.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.774

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RYR2	NM_001035.3	c.8426A>C	p.Gln2809Pro	missense_variant	Exon 56 of 105	ENST00000366574.7	NP_001026.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RYR2	ENST00000366574.7	c.8426A>C	p.Gln2809Pro	missense_variant	Exon 56 of 105	1	NM_001035.3	ENSP00000355533.2
RYR2	ENST00000609119.2	n.8426A>C		non_coding_transcript_exon_variant	Exon 56 of 104	5		ENSP00000499659.2
RYR2	ENST00000660292.2	c.8426A>C	p.Gln2809Pro	missense_variant	Exon 56 of 106			ENSP00000499787.2
RYR2	ENST00000659194.3	c.8426A>C	p.Gln2809Pro	missense_variant	Exon 56 of 105			ENSP00000499653.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jul 02, 2012

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The Gln2809Pro variant in RYR2 has not been reported in the literature, but has been identified in 1 individual with DCM tested by our laboratory. Computational analyses (biochemical amino acid properties, conservation, AlignGVGD, PolyPhen2 , and SIFT) do not provide strong support for or against an impact to the protei n. Additional information is needed to fully assess the clinical significance of this variant. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Pathogenic	0.42	D
BayesDel_noAF	Pathogenic	0.36
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.70	D;T
Eigen	Benign	0.14
Eigen_PC	Uncertain	0.28
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.97	D;D
M_CAP	Pathogenic	0.34	D
MetaRNN	Pathogenic	0.77	D;D
MetaSVM	Uncertain	0.70	D
MutationAssessor	Uncertain	2.0	M;.
PrimateAI	Uncertain	0.68	T
PROVEAN	Uncertain	-3.9	D;.
REVEL	Pathogenic	0.66
Sift	Benign	0.15	T;.
Polyphen		0.091	B;.
Vest4		0.62
MutPred		0.35		Loss of sheet (P = 0.0228);.;
MVP		0.98
MPC		0.45
ClinPred		0.92	D
GERP RS		5.5
Varity_R		0.69
gMVP		0.63

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: rs397516551; hg19: chr1-237824237;