1-237550582-C-T

Variant names:

• chr1-237550582-C-T
• rs747358776
• NM_001035.3:c.3105C>T

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 2P and 10B. PM2 BP4_Strong BP6 BP7 BS2

The NM_001035.3(RYR2):​c.3105C>T​(p.Tyr1035Tyr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000343 in 1,456,120 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: not found (cov: 32)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: RYR2 NM_001035.3 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:3
• Conservation: PhyloP100: -1.39
• Publications: 0 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: Orphanet, ClinGen, G2P
• catecholaminergic polymorphic ventricular tachycardia 1

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• 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 -8 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.75).
• BP6: Variant 1-237550582-C-T is Benign according to our data. Variant chr1-237550582-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 296717.
• BP7: Synonymous conserved (PhyloP=-1.39 with no splicing effect.
• BS2: High AC in GnomAdExome4 at 5 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.3105C>T	p.Tyr1035Tyr	synonymous	Exon 27 of 105	NP_001026.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RYR2	ENST00000366574.7	TSL:1 MANE Select	c.3105C>T	p.Tyr1035Tyr	synonymous	Exon 27 of 105	ENSP00000355533.2
	RYR2	ENST00000661330.2		c.3105C>T	p.Tyr1035Tyr	synonymous	Exon 27 of 106	ENSP00000499393.2
	RYR2	ENST00000609119.2	TSL:5	n.3105C>T		non_coding_transcript_exon	Exon 27 of 104	ENSP00000499659.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000836 AC: 2 AN: 239266 AF XY: 0.00000774

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000299

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000923

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000343 AC: 5 AN: 1456120 Hom.: 0 Cov.: 30 AF XY: 0.00000415 AC XY: 3 AN XY: 723440

African (AFR) AF: 0.00 AC: 0 AN: 33406

American (AMR) AF: 0.0000455 AC: 2 AN: 43966

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25966

East Asian (EAS) AF: 0.00 AC: 0 AN: 39580

South Asian (SAS) AF: 0.00 AC: 0 AN: 84710

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

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5762

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1109336

Other (OTH) AF: 0.00 AC: 0 AN: 60226

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000293 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	1	Catecholaminergic polymorphic ventricular tachycardia 1 (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	-0.75
CADD	Benign	2.3
DANN	Benign	0.89
PhyloP100		-1.4
Mutation Taster		=99/1	polymorphism

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: rs747358776; hg19: chr1-237713882;