rs200574919

Variant names:

• chr1-237590715-A-G
• rs200574919
• NM_001035.3:c.3883A>G

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.3883A>G​(p.Ser1295Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000858 in 1,608,548 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).

• Frequency:
  • Genomes: 𝑓 0.000092 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000085 (0 hom.)
• Consequence: RYR2 NM_001035.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:8 B:3
• Conservation: PhyloP100: 9.32
• 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: 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 -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 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=0.33006063).
• BP6: Variant 1-237590715-A-G is Benign according to our data. Variant chr1-237590715-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 532318.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000092 (14/152188) while in subpopulation NFE AF = 0.000176 (12/68038). AF 95% confidence interval is 0.000102. There are 0 homozygotes in GnomAd4. There are 5 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High AC in GnomAd4 at 14 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.3883A>G	p.Ser1295Gly	missense	Exon 31 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.3883A>G	p.Ser1295Gly	missense	Exon 31 of 105	ENSP00000355533.2	Q92736-1
	RYR2	ENST00000661330.2		c.3883A>G	p.Ser1295Gly	missense	Exon 31 of 106	ENSP00000499393.2	A0A590UJF6
	RYR2	ENST00000609119.2	TSL:5	n.3883A>G		non_coding_transcript_exon	Exon 31 of 104	ENSP00000499659.2	A0A590UK06

Frequencies

GnomAD3 genomes AF: 0.0000920 AC: 14 AN: 152188 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

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: 0.000176

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000814 AC: 20 AN: 245714 AF XY: 0.0000601

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000582

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000162

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000851 AC: 124 AN: 1456360 Hom.: 0 Cov.: 31 AF XY: 0.0000857 AC XY: 62 AN XY: 723730

African (AFR) AF: 0.0000299 AC: 1 AN: 33402

American (AMR) AF: 0.0000674 AC: 3 AN: 44514

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25766

East Asian (EAS) AF: 0.00 AC: 0 AN: 39658

South Asian (SAS) AF: 0.00 AC: 0 AN: 85714

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53168

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5740

European-Non Finnish (NFE) AF: 0.000105 AC: 116 AN: 1108228

Other (OTH) AF: 0.0000665 AC: 4 AN: 60170

GnomAD4 genome AF: 0.0000920 AC: 14 AN: 152188 Hom.: 0 Cov.: 31 AF XY: 0.0000672 AC XY: 5 AN XY: 74352

African (AFR) AF: 0.00 AC: 0 AN: 41450

American (AMR) AF: 0.000131 AC: 2 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

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

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000176 AC: 12 AN: 68038

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.000143 Hom.: 0

Bravo AF: 0.0000680

ExAC AF: 0.0000579 AC: 7

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	3	-	not provided (3)
-	1	1	Cardiomyopathy (2)
-	2	-	Cardiovascular phenotype (2)
-	1	-	Catecholaminergic polymorphic ventricular tachycardia (1)
-	-	1	Catecholaminergic polymorphic ventricular tachycardia 1 (1)
-	1	-	Catecholaminergic polymorphic ventricular tachycardia 1;C1832931:Arrhythmogenic right ventricular dysplasia 2;C5542154:Ventricular arrhythmias due to cardiac ryanodine receptor calcium release deficiency syndrome (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	0.0065	T
BayesDel_noAF	Uncertain	0.030
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.61	D
Eigen	Benign	0.045
Eigen_PC	Benign	0.21
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.82	T
M_CAP	Pathogenic	0.31	D
MetaRNN	Benign	0.33	T
MetaSVM	Uncertain	0.51	D
MutationAssessor	Benign	1.3	L
PhyloP100		9.3
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	-1.9	N
REVEL	Uncertain	0.46
Sift	Benign	0.11	T
Polyphen		0.010	B
Vest4		0.70
MutPred		0.23		Loss of stability (P = 0.0126)
MVP		0.89
MPC		0.36
ClinPred		0.18	T
GERP RS		5.0
Varity_R		0.18
gMVP		0.33
Mutation Taster		=25/75	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs200574919; hg19: chr1-237754015;