rs75901196

chr1-237591774-C-Achr1-237591774-C-T

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 1P and 4B. PP2 BP4_Strong

The NM_001035.3(RYR2):c.4196C>A(p.Thr1399Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00038 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: RYR2 NM_001035.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.68

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 where missense usually causes diseases, RYR2
• BP4: Computational evidence support a benign effect (MetaRNN=0.004270375).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RYR2	NM_001035.3	c.4196C>A	p.Thr1399Lys	missense_variant	32/105	ENST00000366574.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RYR2	ENST00000366574.7	c.4196C>A	p.Thr1399Lys	missense_variant	32/105	1	NM_001035.3	P1
RYR2	ENST00000660292.2	c.4196C>A	p.Thr1399Lys	missense_variant	32/106
RYR2	ENST00000659194.3	c.4196C>A	p.Thr1399Lys	missense_variant	32/105
RYR2	ENST00000609119.2	c.4196C>A	p.Thr1399Lys	missense_variant, NMD_transcript_variant	32/104	5

Frequencies

GnomAD3 genomes AF: 0.00 AC: 0 AN: 152060 Hom.: 0 Cov.: 31 FAILED QC

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.000381 AC: 551 AN: 1447466 Hom.: 0 Cov.: 30 AF XY: 0.000428 AC XY: 308 AN XY: 719212

Gnomad4 AFR exome AF: 0.000850

Gnomad4 AMR exome AF: 0.00431

Gnomad4 ASJ exome AF: 0.000468

Gnomad4 EAS exome AF: 0.00175

Gnomad4 SAS exome AF: 0.000236

Gnomad4 FIN exome AF: 0.00125

Gnomad4 NFE exome AF: 0.000142

Gnomad4 OTH exome AF: 0.000401

GnomAD4 genome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 152172 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 74402

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000719 Hom.: 0

ExAC AF: 0.00764 AC: 923

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Arrhythmogenic right ventricular dysplasia 1 Uncertain:1

Uncertain significance, criteria provided, single submitter

research

CSER _CC_NCGL, University of Washington

Mar 11, 2015

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.29
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Uncertain	-0.060
Cadd	Benign	18
Dann	Benign	0.96
DEOGEN2	Uncertain	0.50	T;T
Eigen	Benign	-0.21
Eigen_PC	Benign	-0.014
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.83	T;T
MetaRNN	Benign	0.0043	T;T
MetaSVM	Uncertain	0.21	D
MutationAssessor	Benign	0.90	L;.
MutationTaster	Benign	0.96	D
PrimateAI	Uncertain	0.50	T
PROVEAN	Uncertain	-2.7	D;.
REVEL	Uncertain	0.37
Sift	Benign	0.23	T;.
Polyphen		0.039	B;.
Vest4		0.56
MVP		0.67
MPC		0.44
ClinPred		0.019	T
GERP RS		5.5
Varity_R		0.26
gMVP		0.52

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: rs75901196; hg19: chr1-237755074; COSMIC: COSV63700316;