chr1-237614744-T-A

Position:

• chr1-237614744-T-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 5P and 4B. PM2 PM5 PP2 BP4_Strong

The ENST00000366574.7(RYR2):​c.5616T>A​(p.Asp1872Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,536 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign 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. D1872N) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: RYR2 ENST00000366574.7 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.284

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
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr1-237614742-G-A is described in Lovd as [Likely_pathogenic].
• 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=0.034005314).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RYR2	NM_001035.3	c.5616T>A	p.Asp1872Glu	missense_variant	37/105	ENST00000366574.7	NP_001026.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RYR2	ENST00000366574.7	c.5616T>A	p.Asp1872Glu	missense_variant	37/105	1	NM_001035.3	ENSP00000355533	P1
RYR2	ENST00000660292.2	c.5616T>A	p.Asp1872Glu	missense_variant	37/106			ENSP00000499787
RYR2	ENST00000659194.3	c.5616T>A	p.Asp1872Glu	missense_variant	37/105			ENSP00000499653
RYR2	ENST00000609119.2	c.5616T>A	p.Asp1872Glu	missense_variant, NMD_transcript_variant	37/104	5		ENSP00000499659

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000807 AC: 2 AN: 247978 Hom.: 0 AF XY: 0.0000149 AC XY: 2 AN XY: 134586

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000654

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461536 Hom.: 0 Cov.: 31 AF XY: 0.00000550 AC XY: 4 AN XY: 727018

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: 0.0000464

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000826 AC: 1

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

Labcorp Genetics (formerly Invitae), Labcorp

May 05, 2022

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. This sequence change replaces aspartic acid, which is acidic and polar, with glutamic acid, which is acidic and polar, at codon 1872 of the RYR2 protein (p.Asp1872Glu). This variant is present in population databases (rs765786213, gnomAD 0.007%). This variant has not been reported in the literature in individuals affected with RYR2-related conditions. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt RYR2 protein function. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.071
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.64
CADD	Benign	0.48
DANN	Benign	0.15
DEOGEN2	Benign	0.32	T;T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.048	N
LIST_S2	Benign	0.63	T;T
M_CAP	Benign	0.071	D
MetaRNN	Benign	0.034	T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	-1.6	N;.
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.35	T
PROVEAN	Benign	0.36	N;.
REVEL	Benign	0.11
Sift	Benign	1.0	T;.
Polyphen		0.0	B;.
Vest4		0.048
MutPred		0.094		Loss of loop (P = 0.0512);.;
MVP		0.39
MPC		0.34
ClinPred		0.038	T
GERP RS		2.7
Varity_R		0.026
gMVP		0.054

Splicing

Name	Calibrated prediction	Score	Prediction
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

LitVar

Other links and lift over

dbSNP: rs765786213; hg19: chr1-237778044;