rs59331340

Variant names:

• chr1-237651484-G-A
• rs59331340
• NM_001035.3:c.7807G>A

Your query was ambiguous. Multiple possible variants found:

• chr1-237651484-G-A
• chr1-237651484-G-C
• chr1-237651484-G-T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 1P and 13B. PP2 BP4_Strong BP6 BS1 BS2

The NM_001035.3(RYR2):​c.7807G>A​(p.Ala2603Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000402 in 1,565,632 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 Conflicting classifications of pathogenicity (no stars). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A2603G) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000041 (0 hom.)
• Consequence: RYR2 NM_001035.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:2
• Conservation: PhyloP100: 1.62
• Publications: 3 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: Orphanet, ClinGen, G2P
• catecholaminergic polymorphic ventricular tachycardia 1

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• 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: Benign. The variant received -12 ACMG points.

• 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=0.0515244).
• BP6: Variant 1-237651484-G-A is Benign according to our data. Variant chr1-237651484-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 191485.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.0000328 (5/152276) while in subpopulation EAS AF = 0.00058 (3/5168). AF 95% confidence interval is 0.000158. There are 0 homozygotes in GnomAd4. There are 2 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 5 AD gene.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RYR2	NM_001035.3	MANE Select	c.7807G>A	p.Ala2603Thr	missense	Exon 51 of 105	NP_001026.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RYR2	ENST00000366574.7	TSL:1 MANE Select	c.7807G>A	p.Ala2603Thr	missense	Exon 51 of 105	ENSP00000355533.2
	RYR2	ENST00000661330.2		c.7807G>A	p.Ala2603Thr	missense	Exon 51 of 106	ENSP00000499393.2
	RYR2	ENST00000609119.2	TSL:5	n.7807G>A		non_coding_transcript_exon	Exon 51 of 104	ENSP00000499659.2

Frequencies

GnomAD3 genomes AF: 0.0000329 AC: 5 AN: 152158 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000579

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000111 AC: 22 AN: 197538 AF XY: 0.000124

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000351

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000769

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000351

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000410 AC: 58 AN: 1413356 Hom.: 0 Cov.: 26 AF XY: 0.0000471 AC XY: 33 AN XY: 700480

African (AFR) AF: 0.00 AC: 0 AN: 32482

American (AMR) AF: 0.0000254 AC: 1 AN: 39358

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25368

East Asian (EAS) AF: 0.000472 AC: 18 AN: 38110

South Asian (SAS) AF: 0.000248 AC: 20 AN: 80544

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51526

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5698

European-Non Finnish (NFE) AF: 0.0000148 AC: 16 AN: 1081546

Other (OTH) AF: 0.0000511 AC: 3 AN: 58724

GnomAD4 genome AF: 0.0000328 AC: 5 AN: 152276 Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2 AN XY: 74468

African (AFR) AF: 0.00 AC: 0 AN: 41562

American (AMR) AF: 0.00 AC: 0 AN: 15300

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

East Asian (EAS) AF: 0.000580 AC: 3 AN: 5168

South Asian (SAS) AF: 0.000415 AC: 2 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68018

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.0000693 Hom.: 0

Bravo AF: 0.0000491

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000122 AC: 1

ExAC AF: 0.0000919 AC: 11

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	3	-	not provided (3)
-	-	1	Cardiomyopathy (1)
-	1	-	Cardiovascular phenotype (1)
-	-	1	Catecholaminergic polymorphic ventricular tachycardia 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.095
BayesDel_addAF	Uncertain	0.050	T
BayesDel_noAF	Benign	-0.17
CADD	Benign	18
DANN	Benign	0.60
DEOGEN2	Benign	0.40	T
Eigen	Benign	-0.27
Eigen_PC	Benign	-0.074
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Benign	0.85	T
M_CAP	Uncertain	0.19	D
MetaRNN	Benign	0.052	T
MetaSVM	Uncertain	0.0041	D
MutationAssessor	Benign	0.48	N
PhyloP100		1.6
PrimateAI	Uncertain	0.72	T
PROVEAN	Benign	-1.6	N
REVEL	Uncertain	0.29
Sift	Benign	1.0	T
Polyphen		0.28	B
Vest4		0.17
MVP		0.70
MPC		0.35
ClinPred		0.036	T
GERP RS		4.3
PromoterAI		-0.0072	Neutral
Varity_R		0.12
gMVP		0.25
Mutation Taster		=55/45	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs59331340; hg19: chr1-237814784;