chr1-237707009-T-A

Position:

• chr1-237707009-T-A

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 1P and 4B. PP2 BS2

The NM_001035.3(RYR2):​c.9641T>A​(p.Leu3214His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000041 in 1,461,672 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. L3214V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: RYR2 NM_001035.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.13

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 Likely_benign. Variant got -3 ACMG points.

• 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.
• BS2: High AC in GnomAdExome4 at 6 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RYR2	NM_001035.3	c.9641T>A	p.Leu3214His	missense_variant	68/105	ENST00000366574.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RYR2	ENST00000366574.7	c.9641T>A	p.Leu3214His	missense_variant	68/105	1	NM_001035.3	P1
RYR2	ENST00000660292.2	c.9641T>A	p.Leu3214His	missense_variant	68/106
RYR2	ENST00000659194.3	c.9641T>A	p.Leu3214His	missense_variant	68/105
RYR2	ENST00000609119.2	c.*676T>A		3_prime_UTR_variant, NMD_transcript_variant	66/104	5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000161 AC: 4 AN: 249124 Hom.: 0 AF XY: 0.0000222 AC XY: 3 AN XY: 135140

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000579

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000177

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000410 AC: 6 AN: 1461672 Hom.: 0 Cov.: 31 AF XY: 0.00000413 AC XY: 3 AN XY: 727116

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

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: 0.00000450

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000312 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.0000165 AC: 2

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

Jul 15, 2022

This variant is present in population databases (rs752385143, gnomAD 0.006%). 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. 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 expected to disrupt RYR2 protein function. ClinVar contains an entry for this variant (Variation ID: 532343). This variant has not been reported in the literature in individuals affected with RYR2-related conditions. This sequence change replaces leucine, which is neutral and non-polar, with histidine, which is basic and polar, at codon 3214 of the RYR2 protein (p.Leu3214His). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.43
BayesDel_addAF	Benign	0.0071	T
BayesDel_noAF	Uncertain	-0.050
CADD	Uncertain	23
DANN	Uncertain	0.98
DEOGEN2	Pathogenic	0.91	D;T
Eigen	Uncertain	0.52
Eigen_PC	Uncertain	0.43
FATHMM_MKL	Benign	0.72	D
LIST_S2	Benign	0.82	T;T
M_CAP	Pathogenic	0.49	D
MetaRNN	Uncertain	0.70	D;D
MetaSVM	Pathogenic	0.92	D
MutationAssessor	Uncertain	2.6	M;.
MutationTaster	Benign	0.96	D
PrimateAI	Uncertain	0.72	T
PROVEAN	Pathogenic	-5.6	D;.
REVEL	Uncertain	0.47
Sift	Pathogenic	0.0	D;.
Polyphen		1.0	D;.
Vest4		0.83
MutPred		0.41		Loss of stability (P = 0.0097);.;
MVP		0.69
MPC		1.2
ClinPred		0.96	D
GERP RS		5.7
Varity_R		0.80
gMVP		0.70

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: rs752385143; hg19: chr1-237870309;