NM_001035.3:c.5656G>A

Variant names:

• chr1-237614784-G-A
• rs3766871
• NM_001035.3:c.5656G>A

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BA1

The NM_001035.3(RYR2):​c.5656G>A​(p.Gly1886Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0374 in 1,609,148 control chromosomes in the GnomAD database, including 1,711 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. G1886A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.061 (447 hom., cov: 32)
  • Exomes 𝑓: 0.035 (1264 hom.)
• Consequence: RYR2 NM_001035.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:15
• Conservation: PhyloP100: 3.45
• Publications: 45 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=0.002141565).
• BP6: Variant 1-237614784-G-A is Benign according to our data. Variant chr1-237614784-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 36747.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.136 is higher than 0.05.

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.5656G>A	p.Gly1886Ser	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.5656G>A	p.Gly1886Ser	missense	Exon 37 of 105	ENSP00000355533.2	Q92736-1
	RYR2	ENST00000661330.2		c.5656G>A	p.Gly1886Ser	missense	Exon 37 of 106	ENSP00000499393.2	A0A590UJF6
	RYR2	ENST00000609119.2	TSL:5	n.5656G>A		non_coding_transcript_exon	Exon 37 of 104	ENSP00000499659.2	A0A590UK06

Frequencies

GnomAD3 genomes AF: 0.0603 AC: 9178 AN: 152122 Hom.: 436 Cov.: 32

Gnomad AFR AF: 0.138

Gnomad AMI AF: 0.00768

Gnomad AMR AF: 0.0320

Gnomad ASJ AF: 0.0236

Gnomad EAS AF: 0.0728

Gnomad SAS AF: 0.0453

Gnomad FIN AF: 0.0215

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.0284

Gnomad OTH AF: 0.0532

GnomAD2 exomes AF: 0.0404 AC: 9914 AN: 245230 AF XY: 0.0391

Gnomad AFR exome AF: 0.143

Gnomad AMR exome AF: 0.0195

Gnomad ASJ exome AF: 0.0196

Gnomad EAS exome AF: 0.0813

Gnomad FIN exome AF: 0.0245

Gnomad NFE exome AF: 0.0306

Gnomad OTH exome AF: 0.0361

GnomAD4 exome AF: 0.0350 AC: 51011 AN: 1456908 Hom.: 1264 Cov.: 32 AF XY: 0.0351 AC XY: 25385 AN XY: 724032

African (AFR) AF: 0.149 AC: 4962 AN: 33276

American (AMR) AF: 0.0216 AC: 960 AN: 44456

Ashkenazi Jewish (ASJ) AF: 0.0187 AC: 484 AN: 25920

East Asian (EAS) AF: 0.0669 AC: 2651 AN: 39614

South Asian (SAS) AF: 0.0418 AC: 3589 AN: 85914

European-Finnish (FIN) AF: 0.0269 AC: 1433 AN: 53246

Middle Eastern (MID) AF: 0.0381 AC: 218 AN: 5728

European-Non Finnish (NFE) AF: 0.0309 AC: 34225 AN: 1108612

Other (OTH) AF: 0.0414 AC: 2489 AN: 60142

GnomAD4 genome AF: 0.0606 AC: 9226 AN: 152240 Hom.: 447 Cov.: 32 AF XY: 0.0591 AC XY: 4400 AN XY: 74450

African (AFR) AF: 0.139 AC: 5778 AN: 41526

American (AMR) AF: 0.0319 AC: 488 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.0236 AC: 82 AN: 3468

East Asian (EAS) AF: 0.0722 AC: 373 AN: 5168

South Asian (SAS) AF: 0.0450 AC: 217 AN: 4826

European-Finnish (FIN) AF: 0.0215 AC: 228 AN: 10626

Middle Eastern (MID) AF: 0.0272 AC: 8 AN: 294

European-Non Finnish (NFE) AF: 0.0284 AC: 1929 AN: 68020

Other (OTH) AF: 0.0550 AC: 116 AN: 2110

Alfa AF: 0.0387 Hom.: 905

Bravo AF: 0.0645

TwinsUK AF: 0.0294 AC: 109

ALSPAC AF: 0.0363 AC: 140

ESP6500AA AF: 0.129 AC: 515

ESP6500EA AF: 0.0311 AC: 259

ExAC AF: 0.0425 AC: 5144

Asia WGS AF: 0.0760 AC: 264 AN: 3478

EpiCase AF: 0.0302

EpiControl AF: 0.0315

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	3	not provided (3)
-	-	2	Cardiomyopathy (2)
-	-	2	Catecholaminergic polymorphic ventricular tachycardia 1 (2)
-	-	1	Arrhythmogenic right ventricular 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	0.076
BayesDel_addAF	Benign	-0.56	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	15
DANN	Benign	0.95
DEOGEN2	Benign	0.33	T
Eigen	Benign	-0.63
Eigen_PC	Benign	-0.53
FATHMM_MKL	Benign	0.76	D
LIST_S2	Benign	0.84	T
MetaRNN	Benign	0.0021	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.69	N
PhyloP100		3.4
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-0.92	N
REVEL	Benign	0.094
Sift	Benign	0.34	T
Polyphen		0.0020	B
Vest4		0.076
MPC		0.36
ClinPred		0.012	T
GERP RS		4.8
Varity_R		0.10
gMVP		0.071
Mutation Taster		=65/35	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: rs3766871; hg19: chr1-237778084; COSMIC: COSV63687181;