NM_001035.3:c.8145G>T

Variant names:

• chr1-237657959-G-T
• rs200420897
• NM_001035.3:c.8145G>T

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 1P and 5B. PP2 BS1_Supporting BS2

The NM_001035.3(RYR2):​c.8145G>T​(p.Glu2715Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000144 in 1,512,072 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. E2715K) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00015 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00014 (0 hom.)
• Consequence: RYR2 NM_001035.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:14 B:1 O:1
• Conservation: PhyloP100: 1.01
• Publications: 6 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: Likely_benign. The variant received -4 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.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000151 (23/152078) while in subpopulation NFE AF = 0.00025 (17/67964). AF 95% confidence interval is 0.000159. There are 0 homozygotes in GnomAd4. There are 13 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High AC in GnomAd4 at 23 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.8145G>T	p.Glu2715Asp	missense	Exon 54 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.8145G>T	p.Glu2715Asp	missense	Exon 54 of 105	ENSP00000355533.2	Q92736-1
	RYR2	ENST00000661330.2		c.8145G>T	p.Glu2715Asp	missense	Exon 54 of 106	ENSP00000499393.2	A0A590UJF6
	RYR2	ENST00000609119.2	TSL:5	n.8145G>T		non_coding_transcript_exon	Exon 54 of 104	ENSP00000499659.2	A0A590UK06

Frequencies

GnomAD3 genomes AF: 0.000151 AC: 23 AN: 151958 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000725

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: 0.000250

Gnomad OTH AF: 0.000480

GnomAD2 exomes AF: 0.000104 AC: 14 AN: 134624 AF XY: 0.0000982

Gnomad AFR exome AF: 0.000153

Gnomad AMR exome AF: 0.000162

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000166

Gnomad OTH exome AF: 0.000274

GnomAD4 exome AF: 0.000143 AC: 194 AN: 1359994 Hom.: 0 Cov.: 25 AF XY: 0.000137 AC XY: 92 AN XY: 670584

African (AFR) AF: 0.0000671 AC: 2 AN: 29824

American (AMR) AF: 0.000132 AC: 4 AN: 30278

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24616

East Asian (EAS) AF: 0.00 AC: 0 AN: 33244

South Asian (SAS) AF: 0.00 AC: 0 AN: 72900

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48856

Middle Eastern (MID) AF: 0.000180 AC: 1 AN: 5558

European-Non Finnish (NFE) AF: 0.000168 AC: 178 AN: 1058242

Other (OTH) AF: 0.000159 AC: 9 AN: 56476

GnomAD4 genome AF: 0.000151 AC: 23 AN: 152078 Hom.: 0 Cov.: 32 AF XY: 0.000175 AC XY: 13 AN XY: 74352

African (AFR) AF: 0.0000723 AC: 3 AN: 41510

American (AMR) AF: 0.000131 AC: 2 AN: 15274

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: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10556

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

European-Non Finnish (NFE) AF: 0.000250 AC: 17 AN: 67964

Other (OTH) AF: 0.000475 AC: 1 AN: 2104

Alfa AF: 0.000222 Hom.: 0

Bravo AF: 0.000132

ESP6500AA AF: 0.000283 AC: 1

ESP6500EA AF: 0.000126 AC: 1

ExAC AF: 0.0000407 AC: 4

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	5	1	not provided (6)
-	2	-	Cardiomyopathy (2)
-	2	-	Catecholaminergic polymorphic ventricular tachycardia 1 (3)
-	1	-	Arrhythmogenic right ventricular dysplasia 2 (1)
-	1	-	Cardiovascular phenotype (1)
-	1	-	Catecholaminergic polymorphic ventricular tachycardia (1)
-	1	-	not specified (1)
-	1	-	Primary dilated cardiomyopathy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.12
CADD	Benign	23
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.63	D
Eigen	Uncertain	0.44
Eigen_PC	Uncertain	0.44
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.94	D
M_CAP	Pathogenic	0.39	D
MetaRNN	Uncertain	0.47	T
MetaSVM	Uncertain	0.40	D
MutationAssessor	Uncertain	2.3	M
PhyloP100		1.0
PrimateAI	Uncertain	0.72	T
PROVEAN	Uncertain	-2.5	D
REVEL	Uncertain	0.50
Sift	Benign	0.22	T
Polyphen		0.98	D
Vest4		0.38
MutPred		0.36		Gain of sheet (P = 0.1208)
MVP		0.92
MPC		1.1
ClinPred		0.30	T
GERP RS		5.0
Varity_R		0.23
gMVP		0.22
Mutation Taster		=40/60	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: rs200420897; hg19: chr1-237821259; COSMIC: COSV63672270;