rs78281932

Variant names:

• chr1-237456734-G-A
• rs78281932
• NM_001035.3:c.1611G>A
• RYR2 p.Leu537Leu

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_001035.3(RYR2):​c.1611G>A​(p.Leu537Leu) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0103 in 1,613,162 control chromosomes in the GnomAD database, including 1,397 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.053 (680 hom., cov: 33)
  • Exomes 𝑓: 0.0059 (717 hom.)
• Consequence: RYR2 NM_001035.3 splice_region, synonymous
• Scores: Splicing: ADA: 0.0002724
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:15
• Conservation: PhyloP100: 0.0810
• Publications: 5 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: Ambry Genetics, Laboratory for Molecular Medicine
• catecholaminergic polymorphic ventricular tachycardia

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, G2P, ClinGen
• 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.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.32).
• BP6: Variant 1-237456734-G-A is Benign according to our data. Variant chr1-237456734-G-A is described in ClinVar as Benign. ClinVar VariationId is 36736.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.081 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.179 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.1611G>A	p.Leu537Leu	splice_region synonymous	Exon 16 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.1611G>A	p.Leu537Leu	splice_region synonymous	Exon 16 of 105	ENSP00000355533.2	Q92736-1
	RYR2	ENST00000661330.2		c.1611G>A	p.Leu537Leu	splice_region synonymous	Exon 16 of 106	ENSP00000499393.2	A0A590UJF6
	RYR2	ENST00000609119.2	TSL:5	n.1611G>A		splice_region non_coding_transcript_exon	Exon 16 of 104	ENSP00000499659.2	A0A590UK06

Frequencies

GnomAD3 genomes AF: 0.0528 AC: 8027 AN: 152066 Hom.: 678 Cov.: 33

Gnomad AFR AF: 0.183

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0211

Gnomad ASJ AF: 0.000865

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00310

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000897

Gnomad OTH AF: 0.0349

GnomAD2 exomes AF: 0.0140 AC: 3484 AN: 248258 AF XY: 0.0107

Gnomad AFR exome AF: 0.190

Gnomad AMR exome AF: 0.00979

Gnomad ASJ exome AF: 0.000698

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000465

Gnomad NFE exome AF: 0.000845

Gnomad OTH exome AF: 0.00731

GnomAD4 exome AF: 0.00585 AC: 8550 AN: 1460978 Hom.: 717 Cov.: 39 AF XY: 0.00509 AC XY: 3696 AN XY: 726778

African (AFR) AF: 0.195 AC: 6527 AN: 33424

American (AMR) AF: 0.0112 AC: 502 AN: 44660

Ashkenazi Jewish (ASJ) AF: 0.000766 AC: 20 AN: 26114

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39690

South Asian (SAS) AF: 0.00245 AC: 211 AN: 86190

European-Finnish (FIN) AF: 0.0000375 AC: 2 AN: 53330

Middle Eastern (MID) AF: 0.0113 AC: 65 AN: 5752

European-Non Finnish (NFE) AF: 0.000442 AC: 491 AN: 1111472

Other (OTH) AF: 0.0121 AC: 731 AN: 60346

GnomAD4 genome AF: 0.0529 AC: 8053 AN: 152184 Hom.: 680 Cov.: 33 AF XY: 0.0511 AC XY: 3802 AN XY: 74400

African (AFR) AF: 0.183 AC: 7576 AN: 41478

American (AMR) AF: 0.0211 AC: 322 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.000865 AC: 3 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5178

South Asian (SAS) AF: 0.00310 AC: 15 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.000897 AC: 61 AN: 68012

Other (OTH) AF: 0.0346 AC: 73 AN: 2112

Alfa AF: 0.0198 Hom.: 604

Bravo AF: 0.0605

Asia WGS AF: 0.0160 AC: 54 AN: 3478

EpiCase AF: 0.00120

EpiControl AF: 0.00119

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.32
CADD	Benign	9.8
DANN	Benign	0.80
PhyloP100		0.081
Mutation Taster		=70/30	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00027
dbscSNV1_RF	Benign	0.11
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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs78281932;

hg19: chr1-237620034;

COSMIC: COSV63672597;