rs1553515428

chr1-237591769-CAGCACA-C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM4 PP3

The NM_001035.3(RYR2):c.4195_4200del(p.Thr1399_Ser1400del) variant causes a inframe deletion change involving the alteration of a conserved nucleotide. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: RYR2 NM_001035.3 inframe_deletion
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.20

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.

• PM4: Nonframeshift variant in NON repetitive region in NM_001035.3.
• PP3: No computational evidence supports a deleterious effect, but strongly conserved according to phyloP

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RYR2	NM_001035.3	c.4195_4200del	p.Thr1399_Ser1400del	inframe_deletion	32/105	ENST00000366574.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RYR2	ENST00000366574.7	c.4195_4200del	p.Thr1399_Ser1400del	inframe_deletion	32/105	1	NM_001035.3	P1
RYR2	ENST00000659194.3	c.4195_4200del	p.Thr1399_Ser1400del	inframe_deletion	32/105
RYR2	ENST00000660292.2	c.4195_4200del	p.Thr1399_Ser1400del	inframe_deletion	32/106
RYR2	ENST00000609119.2	c.4195_4200del	p.Thr1399_Ser1400del	inframe_deletion, NMD_transcript_variant	32/104	5

Frequencies

GnomAD3 genomes Cov.: 31

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Catecholaminergic polymorphic ventricular tachycardia 1 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Dec 04, 2017

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Experimental studies and prediction algorithms are not available for this variant, and the functional significance of the deleted amino acid(s) is currently unknown. This variant has not been reported in the literature in individuals with RYR2-related disease. This variant is not present in population databases (ExAC no frequency). This variant, c.4195_4200delACAAGC, results in the deletion of 2 amino acid(s) of the RYR2 protein (p.Thr1399_Ser1400del), but otherwise preserves the integrity of the reading frame. -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs1553515428; hg19: chr1-237755069;