rs201500134

Variant names:

• chr1-237657976-T-C
• rs201500134
• NM_001035.3:c.8162T>C

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 1P and 11B. PP2 BP4_Moderate BP6 BS1 BS2

The NM_001035.3(RYR2):​c.8162T>C​(p.Ile2721Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0013 in 1,519,710 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I2721L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00064 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0014 (6 hom.)
• Consequence: RYR2 NM_001035.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6 B:14
• Conservation: PhyloP100: 2.82
• Publications: 8 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 -10 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=0.17361951).
• BP6: Variant 1-237657976-T-C is Benign according to our data. Variant chr1-237657976-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 43828.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000644 (98/152182) while in subpopulation NFE AF = 0.00131 (89/67972). AF 95% confidence interval is 0.00109. There are 0 homozygotes in GnomAd4. There are 39 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 98 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.8162T>C	p.Ile2721Thr	missense	Exon 54 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.8162T>C	p.Ile2721Thr	missense	Exon 54 of 105	ENSP00000355533.2
	RYR2	ENST00000661330.2		c.8162T>C	p.Ile2721Thr	missense	Exon 54 of 106	ENSP00000499393.2
	RYR2	ENST00000609119.2	TSL:5	n.8162T>C		non_coding_transcript_exon	Exon 54 of 104	ENSP00000499659.2

Frequencies

GnomAD3 genomes AF: 0.000644 AC: 98 AN: 152064 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000193

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: 0.0000945

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00131

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000575 AC: 79 AN: 137332 AF XY: 0.000577

Gnomad AFR exome AF: 0.000148

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000421

Gnomad NFE exome AF: 0.00124

Gnomad OTH exome AF: 0.000536

GnomAD4 exome AF: 0.00138 AC: 1881 AN: 1367528 Hom.: 6 Cov.: 26 AF XY: 0.00137 AC XY: 922 AN XY: 674114

African (AFR) AF: 0.000133 AC: 4 AN: 30066

American (AMR) AF: 0.0000325 AC: 1 AN: 30806

Ashkenazi Jewish (ASJ) AF: 0.0000405 AC: 1 AN: 24710

East Asian (EAS) AF: 0.00 AC: 0 AN: 33496

South Asian (SAS) AF: 0.00 AC: 0 AN: 73638

European-Finnish (FIN) AF: 0.000572 AC: 28 AN: 48988

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5606

European-Non Finnish (NFE) AF: 0.00170 AC: 1809 AN: 1063492

Other (OTH) AF: 0.000670 AC: 38 AN: 56726

GnomAD4 genome AF: 0.000644 AC: 98 AN: 152182 Hom.: 0 Cov.: 33 AF XY: 0.000524 AC XY: 39 AN XY: 74400

African (AFR) AF: 0.000192 AC: 8 AN: 41572

American (AMR) AF: 0.00 AC: 0 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4820

European-Finnish (FIN) AF: 0.0000945 AC: 1 AN: 10582

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

European-Non Finnish (NFE) AF: 0.00131 AC: 89 AN: 67972

Other (OTH) AF: 0.00 AC: 0 AN: 2110

Alfa AF: 0.000956 Hom.: 0

Bravo AF: 0.000676

TwinsUK AF: 0.00270 AC: 10

ALSPAC AF: 0.00208 AC: 8

ESP6500AA AF: 0.000560 AC: 2

ESP6500EA AF: 0.000502 AC: 4

ExAC AF: 0.000244 AC: 25

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	5	not provided (5)
-	3	2	not specified (5)
-	-	2	Cardiomyopathy (2)
-	-	2	Catecholaminergic polymorphic ventricular tachycardia 1 (2)
-	1	-	Arrhythmogenic right ventricular cardiomyopathy (1)
-	1	-	Arrhythmogenic right ventricular dysplasia 2 (1)
-	-	1	Cardiovascular phenotype (1)
-	-	1	Catecholaminergic polymorphic ventricular tachycardia (1)
-	-	1	RYR2-related disorder (1)
-	1	-	Wolff-Parkinson-White pattern (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.38
BayesDel_addAF	Benign	-0.10	T
BayesDel_noAF	Uncertain	0.070
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.83	D
Eigen	Uncertain	0.43
Eigen_PC	Uncertain	0.52
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.91	D
M_CAP	Uncertain	0.19	D
MetaRNN	Benign	0.17	T
MetaSVM	Uncertain	0.50	D
MutationAssessor	Benign	0.84	L
PhyloP100		2.8
PrimateAI	Uncertain	0.78	T
PROVEAN	Uncertain	-3.6	D
REVEL	Uncertain	0.59
Sift	Benign	0.17	T
Polyphen		0.85	P
Vest4		0.65
MVP		0.78
MPC		1.2
ClinPred		0.10	T
GERP RS		6.2
Varity_R		0.28
gMVP		0.43
Mutation Taster		=30/70	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: rs201500134; hg19: chr1-237821276;