rs397516535

Positions:

• chr1-237610801-C-A
• chr1-237610801-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_001035.3(RYR2):​c.4723C>A​(p.His1575Asn) 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 benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H1575Y) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: RYR2 NM_001035.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.97

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 1 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.
• BP4: Computational evidence support a benign effect (MetaRNN=0.25328985).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RYR2	NM_001035.3	c.4723C>A	p.His1575Asn	missense_variant	36/105	ENST00000366574.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RYR2	ENST00000366574.7	c.4723C>A	p.His1575Asn	missense_variant	36/105	1	NM_001035.3	P1
RYR2	ENST00000660292.2	c.4723C>A	p.His1575Asn	missense_variant	36/106
RYR2	ENST00000659194.3	c.4723C>A	p.His1575Asn	missense_variant	36/105
RYR2	ENST00000609119.2	c.4723C>A	p.His1575Asn	missense_variant, NMD_transcript_variant	36/104	5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1457526 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 724670

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Uncertain	-0.050
CADD	Benign	20
DANN	Benign	0.97
DEOGEN2	Uncertain	0.43	T;T
Eigen	Benign	-0.054
Eigen_PC	Benign	0.13
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Benign	0.82	T;T
M_CAP	Benign	0.045	D
MetaRNN	Benign	0.25	T;T
MetaSVM	Uncertain	0.34	D
MutationAssessor	Benign	1.2	L;.
MutationTaster	Benign	0.78	D
PrimateAI	Uncertain	0.75	T
PROVEAN	Benign	-1.3	N;.
REVEL	Benign	0.27
Sift	Benign	0.16	T;.
Polyphen		0.0030	B;.
Vest4		0.59
MutPred		0.20		Gain of ubiquitination at K1572 (P = 0.0918);.;
MVP		0.75
MPC		0.42
ClinPred		0.57	D
GERP RS		5.2
Varity_R		0.16
gMVP		0.13

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: rs397516535; hg19: chr1-237774101;