rs72549415

Variant names:

• chr1-237566759-C-T
• rs72549415
• NM_001035.3:c.3407C>T

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001035.3(RYR2):​c.3407C>T​(p.Ala1136Val) variant causes a missense change. The variant allele was found at a frequency of 0.00996 in 1,613,936 control chromosomes in the GnomAD database, including 128 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. A1136A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0072 (10 hom., cov: 33)
  • Exomes 𝑓: 0.010 (118 hom.)
• Consequence: RYR2 NM_001035.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:23
• Conservation: PhyloP100: 4.02
• Publications: 19 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: Benign. The variant received -19 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 arrhythmogenic right ventricular cardiomyopathy, hypertrophic cardiomyopathy, arrhythmogenic right ventricular dysplasia 2, catecholaminergic polymorphic ventricular tachycardia 1, catecholaminergic polymorphic ventricular tachycardia, dilated cardiomyopathy.
• BP4: Computational evidence support a benign effect (MetaRNN=0.010338664).
• BP6: Variant 1-237566759-C-T is Benign according to our data. Variant chr1-237566759-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 43770.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00715 (1089/152282) while in subpopulation NFE AF = 0.0128 (873/68028). AF 95% confidence interval is 0.0121. There are 10 homozygotes in GnomAd4. There are 487 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1089 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RYR2	NM_001035.3	MANE Select	c.3407C>T	p.Ala1136Val	missense	Exon 28 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.3407C>T	p.Ala1136Val	missense	Exon 28 of 105	ENSP00000355533.2	Q92736-1
	RYR2	ENST00000661330.2		c.3407C>T	p.Ala1136Val	missense	Exon 28 of 106	ENSP00000499393.2	A0A590UJF6
	RYR2	ENST00000609119.2	TSL:5	n.3407C>T		non_coding_transcript_exon	Exon 28 of 104	ENSP00000499659.2	A0A590UK06

Frequencies

GnomAD3 genomes AF: 0.00716 AC: 1089 AN: 152164 Hom.: 10 Cov.: 33

Gnomad AFR AF: 0.00224

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00400

Gnomad ASJ AF: 0.00231

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00405

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0128

Gnomad OTH AF: 0.00430

GnomAD2 exomes AF: 0.00683 AC: 1701 AN: 249104 AF XY: 0.00653

Gnomad AFR exome AF: 0.00155

Gnomad AMR exome AF: 0.00240

Gnomad ASJ exome AF: 0.00338

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00441

Gnomad NFE exome AF: 0.0123

Gnomad OTH exome AF: 0.00694

GnomAD4 exome AF: 0.0103 AC: 14986 AN: 1461654 Hom.: 118 Cov.: 31 AF XY: 0.0100 AC XY: 7270 AN XY: 727108

African (AFR) AF: 0.00158 AC: 53 AN: 33474

American (AMR) AF: 0.00246 AC: 110 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00341 AC: 89 AN: 26130

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.00105 AC: 91 AN: 86256

European-Finnish (FIN) AF: 0.00588 AC: 314 AN: 53402

Middle Eastern (MID) AF: 0.00243 AC: 14 AN: 5766

European-Non Finnish (NFE) AF: 0.0125 AC: 13860 AN: 1111830

Other (OTH) AF: 0.00752 AC: 454 AN: 60372

GnomAD4 genome AF: 0.00715 AC: 1089 AN: 152282 Hom.: 10 Cov.: 33 AF XY: 0.00654 AC XY: 487 AN XY: 74460

African (AFR) AF: 0.00224 AC: 93 AN: 41564

American (AMR) AF: 0.00399 AC: 61 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00231 AC: 8 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00405 AC: 43 AN: 10612

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.0128 AC: 873 AN: 68028

Other (OTH) AF: 0.00426 AC: 9 AN: 2114

Alfa AF: 0.00940 Hom.: 20

Bravo AF: 0.00643

TwinsUK AF: 0.0143 AC: 53

ALSPAC AF: 0.0104 AC: 40

ESP6500AA AF: 0.00239 AC: 10

ESP6500EA AF: 0.0130 AC: 110

ExAC AF: 0.00705 AC: 853

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00992

EpiControl AF: 0.0110

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	8	not provided (8)
-	-	7	not specified (7)
-	-	3	Cardiomyopathy (3)
-	-	2	Catecholaminergic polymorphic ventricular tachycardia 1 (2)
-	-	1	Arrhythmogenic right ventricular dysplasia 2 (1)
-	-	1	Cardiovascular phenotype (1)
-	-	1	Catecholaminergic polymorphic ventricular tachycardia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.073
BayesDel_addAF	Benign	-0.54	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	23
DANN	Benign	0.90
DEOGEN2	Benign	0.35	T
Eigen	Benign	-0.34
Eigen_PC	Benign	-0.062
FATHMM_MKL	Benign	0.72	D
LIST_S2	Uncertain	0.87	D
MetaRNN	Benign	0.010	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	-0.29	N
PhyloP100		4.0
PrimateAI	Uncertain	0.63	T
PROVEAN	Benign	1.3	N
REVEL	Benign	0.073
Sift	Benign	0.77	T
Polyphen		0.0	B
Vest4		0.36
MVP		0.25
MPC		0.36
ClinPred		0.0074	T
GERP RS		5.3
Varity_R		0.044
gMVP		0.81
Mutation Taster		=42/58	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: rs72549415; hg19: chr1-237730059;