chr1-237707209-T-G

Position:

• chr1-237707209-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP2

The ENST00000366574.7(RYR2):​c.9841T>G​(p.Leu3281Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000691 in 1,447,096 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. L3281L) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: RYR2 ENST00000366574.7 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.196

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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), RYR2. . Gene score misZ 5.7809 (greater than the threshold 3.09). Trascript score misZ 6.4158 (greater than threshold 3.09). GenCC has associacion of gene with hypertrophic cardiomyopathy, arrhythmogenic right ventricular cardiomyopathy, catecholaminergic polymorphic ventricular tachycardia 1, arrhythmogenic right ventricular dysplasia 2, catecholaminergic polymorphic ventricular tachycardia.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RYR2	NM_001035.3	c.9841T>G	p.Leu3281Val	missense_variant	68/105	ENST00000366574.7	NP_001026.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RYR2	ENST00000366574.7	c.9841T>G	p.Leu3281Val	missense_variant	68/105	1	NM_001035.3	ENSP00000355533	P1
RYR2	ENST00000660292.2	c.9841T>G	p.Leu3281Val	missense_variant	68/106			ENSP00000499787
RYR2	ENST00000659194.3	c.9841T>G	p.Leu3281Val	missense_variant	68/105			ENSP00000499653
RYR2	ENST00000609119.2	c.*876T>G		3_prime_UTR_variant, NMD_transcript_variant	66/104	5		ENSP00000499659

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.91e-7 AC: 1 AN: 1447096 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 717266

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.08e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

research

Biesecker Lab/Clinical Genomics Section, National Institutes of Health

Jun 24, 2013

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.51
BayesDel_addAF	Benign	-0.019	T
BayesDel_noAF	Benign	-0.26
CADD	Benign	7.2
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.92	D;D
Eigen	Benign	-0.25
Eigen_PC	Benign	-0.40
FATHMM_MKL	Benign	0.23	N
LIST_S2	Pathogenic	0.99	D;D
M_CAP	Pathogenic	0.55	D
MetaRNN	Uncertain	0.60	D;D
MetaSVM	Pathogenic	0.84	D
MutationAssessor	Uncertain	2.8	M;.
MutationTaster	Benign	0.75	N
PrimateAI	Pathogenic	0.84	D
PROVEAN	Uncertain	-2.6	D;.
REVEL	Uncertain	0.57
Sift	Uncertain	0.0020	D;.
Polyphen		0.98	D;.
Vest4		0.61
MutPred		0.52		Gain of methylation at K3282 (P = 0.0352);.;
MVP		0.58
MPC		0.95
ClinPred		0.99	D
GERP RS		-1.4
Varity_R		0.37
gMVP		0.71

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: rs786205424; hg19: chr1-237870509;