NM_001035.3:c.5654G>A

Variant names:

• chr1-237614782-G-A
• rs41315858
• NM_001035.3:c.5654G>A

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.5654G>A​(p.Gly1885Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0233 in 1,609,734 control chromosomes in the GnomAD database, including 537 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G1885A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.017 (25 hom., cov: 32)
  • Exomes 𝑓: 0.024 (512 hom.)
• Consequence: RYR2 NM_001035.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:21
• Conservation: PhyloP100: 0.388
• Publications: 25 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 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=0.0018713474).
• BP6: Variant 1-237614782-G-A is Benign according to our data. Variant chr1-237614782-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 36746.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 = 0.0171 (2599/152334) while in subpopulation NFE AF = 0.0282 (1921/68024). AF 95% confidence interval is 0.0272. There are 25 homozygotes in GnomAd4. There are 1194 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 2599 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.5654G>A	p.Gly1885Glu	missense	Exon 37 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.5654G>A	p.Gly1885Glu	missense	Exon 37 of 105	ENSP00000355533.2	Q92736-1
	RYR2	ENST00000661330.2		c.5654G>A	p.Gly1885Glu	missense	Exon 37 of 106	ENSP00000499393.2	A0A590UJF6
	RYR2	ENST00000609119.2	TSL:5	n.5654G>A		non_coding_transcript_exon	Exon 37 of 104	ENSP00000499659.2	A0A590UK06

Frequencies

GnomAD3 genomes AF: 0.0171 AC: 2600 AN: 152216 Hom.: 25 Cov.: 32

Gnomad AFR AF: 0.00533

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0161

Gnomad ASJ AF: 0.00778

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000828

Gnomad FIN AF: 0.0140

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0283

Gnomad OTH AF: 0.0148

GnomAD2 exomes AF: 0.0156 AC: 3828 AN: 245448 AF XY: 0.0154

Gnomad AFR exome AF: 0.00431

Gnomad AMR exome AF: 0.00874

Gnomad ASJ exome AF: 0.00830

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0150

Gnomad NFE exome AF: 0.0263

Gnomad OTH exome AF: 0.0180

GnomAD4 exome AF: 0.0239 AC: 34852 AN: 1457400 Hom.: 512 Cov.: 31 AF XY: 0.0232 AC XY: 16835 AN XY: 724356

African (AFR) AF: 0.00342 AC: 114 AN: 33300

American (AMR) AF: 0.00888 AC: 395 AN: 44464

Ashkenazi Jewish (ASJ) AF: 0.00721 AC: 187 AN: 25948

East Asian (EAS) AF: 0.0000505 AC: 2 AN: 39626

South Asian (SAS) AF: 0.00173 AC: 149 AN: 85948

European-Finnish (FIN) AF: 0.0149 AC: 793 AN: 53260

Middle Eastern (MID) AF: 0.00401 AC: 23 AN: 5734

European-Non Finnish (NFE) AF: 0.0289 AC: 32028 AN: 1108950

Other (OTH) AF: 0.0193 AC: 1161 AN: 60170

GnomAD4 genome AF: 0.0171 AC: 2599 AN: 152334 Hom.: 25 Cov.: 32 AF XY: 0.0160 AC XY: 1194 AN XY: 74484

African (AFR) AF: 0.00531 AC: 221 AN: 41582

American (AMR) AF: 0.0161 AC: 246 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00778 AC: 27 AN: 3472

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

South Asian (SAS) AF: 0.000829 AC: 4 AN: 4828

European-Finnish (FIN) AF: 0.0140 AC: 149 AN: 10622

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

European-Non Finnish (NFE) AF: 0.0282 AC: 1921 AN: 68024

Other (OTH) AF: 0.0147 AC: 31 AN: 2112

Alfa AF: 0.0220 Hom.: 101

Bravo AF: 0.0161

TwinsUK AF: 0.0337 AC: 125

ALSPAC AF: 0.0306 AC: 118

ESP6500AA AF: 0.00526 AC: 21

ESP6500EA AF: 0.0234 AC: 195

ExAC AF: 0.0149 AC: 1803

Asia WGS AF: 0.00375 AC: 13 AN: 3478

EpiCase AF: 0.0264

EpiControl AF: 0.0256

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	8	not specified (8)
-	-	6	not provided (6)
-	-	2	Catecholaminergic polymorphic ventricular tachycardia 1 (2)
-	-	1	Arrhythmogenic right ventricular cardiomyopathy (1)
-	-	1	Arrhythmogenic right ventricular dysplasia 2 (1)
-	-	1	Cardiomyopathy (1)
-	-	1	Cardiovascular phenotype (1)
-	-	1	Catecholaminergic polymorphic ventricular tachycardia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.074
BayesDel_addAF	Benign	-0.55	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	4.4
DANN	Benign	0.50
DEOGEN2	Benign	0.33	T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.037	N
LIST_S2	Benign	0.81	T
MetaRNN	Benign	0.0019	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	0.60	N
PhyloP100		0.39
PrimateAI	Benign	0.32	T
PROVEAN	Benign	0.55	N
REVEL	Benign	0.090
Sift	Benign	0.89	T
Polyphen		0.0	B
Vest4		0.067
MPC		0.47
ClinPred		0.0052	T
GERP RS		-2.4
Varity_R		0.049
gMVP		0.11
Mutation Taster		=88/12	polymorphism (auto)

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: rs41315858; hg19: chr1-237778082;