rs1553283030

Variant names:

• chr1-237687456-C-G
• NM_001035.3:c.9019C>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.9019C>G​(p.Leu3007Val) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.000000707 in 1,415,266 control chromosomes in the GnomAD database, with no homozygous occurrence. 2/3 splice prediction tools predicting alterations to normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. L3007L) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
• Consequence: RYR2 NM_001035.3 missense, splice_region
• Scores: Splicing: ADA: 0.9690
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.84

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: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RYR2	NM_001035.3	c.9019C>G	p.Leu3007Val	missense_variant, splice_region_variant	Exon 63 of 105	ENST00000366574.7	NP_001026.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RYR2	ENST00000366574.7	c.9019C>G	p.Leu3007Val	missense_variant, splice_region_variant	Exon 63 of 105	1	NM_001035.3	ENSP00000355533.2
RYR2	ENST00000609119.2	n.*102+6879C>G		intron_variant	Intron 61 of 103	5		ENSP00000499659.2
RYR2	ENST00000660292.2	c.9019C>G	p.Leu3007Val	missense_variant, splice_region_variant	Exon 63 of 106			ENSP00000499787.2
RYR2	ENST00000659194.3	c.9019C>G	p.Leu3007Val	missense_variant, splice_region_variant	Exon 63 of 105			ENSP00000499653.3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 7.07e-7 AC: 1 AN: 1415266 Hom.: 0 Cov.: 30 AF XY: 0.00000142 AC XY: 1 AN XY: 703884

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: 0.0000118

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.28
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.060
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.92	D;D
Eigen	Uncertain	0.67
Eigen_PC	Pathogenic	0.68
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.90	D;D
M_CAP	Pathogenic	0.69	D
MetaRNN	Uncertain	0.62	D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.0	M;.
PrimateAI	Pathogenic	0.82	D
PROVEAN	Benign	-2.3	N;.
REVEL	Uncertain	0.59
Sift	Uncertain	0.0020	D;.
Polyphen		0.93	P;.
Vest4		0.43
MutPred		0.27		Loss of ubiquitination at K3010 (P = 0.1231);.;
MVP		0.77
MPC		0.82
ClinPred		0.93	D
GERP RS		5.6
Varity_R		0.37
gMVP		0.47

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.97
dbscSNV1_RF	Pathogenic	0.75
SpliceAI score (max)		0.040		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-237850756;