chr1-237784631-C-T

Variant names:

• chr1-237784631-C-T
• rs200092869
• NM_001035.3:c.12919C>T

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 1P and 10B. PP2 BP4 BP6 BS1 BS2

The NM_001035.3(RYR2):​c.12919C>T​(p.Arg4307Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000643 in 1,613,548 control chromosomes in the GnomAD database, including 2 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. R4307H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00039 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00067 (2 hom.)
• Consequence: RYR2 NM_001035.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:10
• Conservation: PhyloP100: 1.16
• Publications: 11 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

ENSG00000296715 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -9 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=0.28710905).
• BP6: Variant 1-237784631-C-T is Benign according to our data. Variant chr1-237784631-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 191546.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000388 (59/152030) while in subpopulation NFE AF = 0.000706 (48/67998). AF 95% confidence interval is 0.000547. There are 0 homozygotes in GnomAd4. There are 25 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 59 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.12919C>T	p.Arg4307Cys	missense	Exon 90 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.12919C>T	p.Arg4307Cys	missense	Exon 90 of 105	ENSP00000355533.2
	RYR2	ENST00000661330.2		c.12943C>T	p.Arg4315Cys	missense	Exon 91 of 106	ENSP00000499393.2
	RYR2	ENST00000609119.2	TSL:5	n.*4011C>T		non_coding_transcript_exon	Exon 89 of 104	ENSP00000499659.2

Frequencies

GnomAD3 genomes AF: 0.000388 AC: 59 AN: 152030 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000966

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000328

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: 0.000706

Gnomad OTH AF: 0.000958

GnomAD2 exomes AF: 0.000346 AC: 86 AN: 248746 AF XY: 0.000348

Gnomad AFR exome AF: 0.000129

Gnomad AMR exome AF: 0.000261

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000648

Gnomad OTH exome AF: 0.000332

GnomAD4 exome AF: 0.000670 AC: 979 AN: 1461518 Hom.: 2 Cov.: 33 AF XY: 0.000627 AC XY: 456 AN XY: 727050

African (AFR) AF: 0.0000897 AC: 3 AN: 33438

American (AMR) AF: 0.000358 AC: 16 AN: 44690

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.00 AC: 0 AN: 86254

European-Finnish (FIN) AF: 0.0000562 AC: 3 AN: 53398

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.000825 AC: 917 AN: 1111778

Other (OTH) AF: 0.000663 AC: 40 AN: 60362

GnomAD4 genome AF: 0.000388 AC: 59 AN: 152030 Hom.: 0 Cov.: 32 AF XY: 0.000337 AC XY: 25 AN XY: 74242

African (AFR) AF: 0.0000966 AC: 4 AN: 41418

American (AMR) AF: 0.000328 AC: 5 AN: 15258

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5168

South Asian (SAS) AF: 0.00 AC: 0 AN: 4814

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10590

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.000706 AC: 48 AN: 67998

Other (OTH) AF: 0.000958 AC: 2 AN: 2088

Alfa AF: 0.000420 Hom.: 0

Bravo AF: 0.000499

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00109 AC: 9

ExAC AF: 0.000223 AC: 27

EpiCase AF: 0.000545

EpiControl AF: 0.000533

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.19
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.78	D
Eigen	Uncertain	0.39
Eigen_PC	Uncertain	0.34
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Uncertain	0.97	D
M_CAP	Uncertain	0.10	D
MetaRNN	Benign	0.29	T
MetaSVM	Uncertain	0.52	D
MutationAssessor	Benign	2.0	M
PhyloP100		1.2
PrimateAI	Uncertain	0.52	T
PROVEAN	Uncertain	-2.6	D
REVEL	Uncertain	0.48
Sift	Benign	0.18	T
Polyphen		1.0	D
Vest4		0.78
MVP		0.68
MPC		1.9
ClinPred		0.087	T
GERP RS		5.1
Varity_R		0.15
gMVP		0.60
Mutation Taster		=94/6	polymorphism

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: rs200092869; hg19: chr1-237947931; COSMIC: COSV63719666;