rs1036775644

Variant names:

• chr1-237742336-T-A
• rs1036775644
• NM_001035.3:c.11132T>A

Your query was ambiguous. Multiple possible variants found:

• chr1-237742336-T-A
• chr1-237742336-T-C
• chr1-237742336-T-G

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 3P and 2B. PM2 PP2 BP4 BS1_Supporting

The NM_001035.3(RYR2):​c.11132T>A​(p.Val3711Glu) variant causes a missense change. The variant allele was found at a frequency of 0.0000264 in 151,292 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts 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. V3711M) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: RYR2 NM_001035.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:4
• Conservation: PhyloP100: 4.92
• Publications: 0 publications found

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]

RYR2 Gene-Disease associations (from GenCC):

• arrhythmogenic right ventricular dysplasia 2

  Inheritance: AD Classification: DEFINITIVE, NO_KNOWN Submitted by: Laboratory for Molecular Medicine, Ambry Genetics
• catecholaminergic polymorphic ventricular tachycardia

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, G2P, Orphanet
• catecholaminergic polymorphic ventricular tachycardia 1

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• dilated cardiomyopathy

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen
• hypertrophic cardiomyopathy

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen
• arrhythmogenic right ventricular cardiomyopathy

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the RYR2 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 195 curated pathogenic missense variants (we use a threshold of 10). The gene has 55 curated benign missense variants. Gene score misZ: 5.7809 (above the threshold of 3.09). Trascript score misZ: 6.4158 (above the threshold of 3.09). GenCC associations: The gene is linked to hypertrophic cardiomyopathy, catecholaminergic polymorphic ventricular tachycardia 1, catecholaminergic polymorphic ventricular tachycardia, arrhythmogenic right ventricular dysplasia 2, arrhythmogenic right ventricular cardiomyopathy.
• BP4: Computational evidence support a benign effect (MetaRNN=0.33187807).
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0000264 (4/151292) while in subpopulation AFR AF = 0.0000973 (4/41124). AF 95% confidence interval is 0.0000327. There are 0 homozygotes in GnomAd4. There are 0 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001035.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RYR2	NM_001035.3	MANE Select	c.11132T>A	p.Val3711Glu	missense	Exon 80 of 105	NP_001026.2	Q92736-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RYR2	ENST00000366574.7	TSL:1 MANE Select	c.11132T>A	p.Val3711Glu	missense	Exon 80 of 105	ENSP00000355533.2	Q92736-1
	RYR2	ENST00000661330.2		c.11132T>A	p.Val3711Glu	missense	Exon 80 of 106	ENSP00000499393.2	A0A590UJF6
	RYR2	ENST00000609119.2	TSL:5	n.*2167T>A		non_coding_transcript_exon	Exon 78 of 104	ENSP00000499659.2	A0A590UK06

Frequencies

GnomAD3 genomes AF: 0.0000264 AC: 4 AN: 151292 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000973

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: AC0 AF: 0.00 AC: 0 AN: 1416678 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 701672

African (AFR) AF: 0.00 AC: 0 AN: 32586

American (AMR) AF: 0.00 AC: 0 AN: 39490

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25452

East Asian (EAS) AF: 0.00 AC: 0 AN: 38426

South Asian (SAS) AF: 0.00 AC: 0 AN: 81014

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51152

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5360

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1084500

Other (OTH) AF: 0.00 AC: 0 AN: 58698

GnomAD4 genome AF: 0.0000264 AC: 4 AN: 151292 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 73804

African (AFR) AF: 0.0000973 AC: 4 AN: 41124

American (AMR) AF: 0.00 AC: 0 AN: 15108

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5140

South Asian (SAS) AF: 0.00 AC: 0 AN: 4802

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10448

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 312

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67908

Other (OTH) AF: 0.00 AC: 0 AN: 2074

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Cardiovascular phenotype (1)
-	1	-	Catecholaminergic polymorphic ventricular tachycardia 1 (1)
-	1	-	not provided (1)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Pathogenic	0.14
CADD	Benign	22
DANN	Benign	0.81
DEOGEN2	Benign	0.33	T
Eigen	Benign	-0.53
Eigen_PC	Benign	-0.17
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.87	D
M_CAP	Uncertain	0.24	D
MetaRNN	Benign	0.33	T
MetaSVM	Uncertain	-0.15	T
MutationAssessor	Benign	-0.95	N
PhyloP100		4.9
PrimateAI	Pathogenic	0.86	D
PROVEAN	Benign	1.1	N
REVEL	Uncertain	0.47
Sift	Benign	1.0	T
Polyphen		0.019	B
Vest4		0.50
MVP		0.93
MPC		1.3
ClinPred		0.88	D
GERP RS		5.9
Varity_R		0.26
gMVP		0.15
Mutation Taster		=46/54	disease causing

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

Other links and lift over

dbSNP: rs1036775644; hg19: chr1-237905636;