1-237786034-C-T

Variant names:

• chr1-237786034-C-T
• rs768161152
• NM_001035.3:c.13326C>T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BS1 BS2

The ENST00000366574.7(RYR2):​c.13326C>T​(p.Ala4442Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000344 in 1,571,630 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: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000037 (0 hom.)
• Consequence: RYR2 ENST00000366574.7 synonymous
• Scores: Splicing: ADA: 0.05044
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:5
• Conservation: PhyloP100: -3.61
• 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

ENSG00000296715 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.6).
• BP6: Variant 1-237786034-C-T is Benign according to our data. Variant chr1-237786034-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 227909.
• BP7: Synonymous conserved (PhyloP=-3.61 with no splicing effect.
• BS1: Variant frequency is greater than expected in population eas. GnomAdExome4 allele frequency = 0.0000366 (52/1419552) while in subpopulation EAS AF = 0.000207 (8/38678). AF 95% confidence interval is 0.000103. There are 0 homozygotes in GnomAdExome4. There are 24 alleles in the male GnomAdExome4 subpopulation. Median coverage is 27. This position passed quality control check.
• BS2: High AC in GnomAdExome4 at 52 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000366574.7. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RYR2	NM_001035.3	MANE Select	c.13326C>T	p.Ala4442Ala	synonymous	Exon 91 of 105	NP_001026.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RYR2	ENST00000366574.7	TSL:1 MANE Select	c.13326C>T	p.Ala4442Ala	synonymous	Exon 91 of 105	ENSP00000355533.2
	RYR2	ENST00000661330.2		c.13344C>T	p.Ala4448Ala	synonymous	Exon 92 of 106	ENSP00000499393.2
	RYR2	ENST00000609119.2	TSL:5	n.*4418C>T		non_coding_transcript_exon	Exon 90 of 104	ENSP00000499659.2

Frequencies

GnomAD3 genomes AF: 0.0000132 AC: 2 AN: 152078 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000452 AC: 9 AN: 198984 AF XY: 0.0000188

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000348

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000409

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000119

Gnomad OTH exome AF: 0.000190

GnomAD4 exome AF: 0.0000366 AC: 52 AN: 1419552 Hom.: 0 Cov.: 27 AF XY: 0.0000341 AC XY: 24 AN XY: 703980

African (AFR) AF: 0.0000307 AC: 1 AN: 32592

American (AMR) AF: 0.0000252 AC: 1 AN: 39694

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25480

East Asian (EAS) AF: 0.000207 AC: 8 AN: 38678

South Asian (SAS) AF: 0.0000122 AC: 1 AN: 81646

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51792

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5712

European-Non Finnish (NFE) AF: 0.0000184 AC: 20 AN: 1084918

Other (OTH) AF: 0.000356 AC: 21 AN: 59040

GnomAD4 genome AF: 0.0000132 AC: 2 AN: 152078 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74292

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 41394

American (AMR) AF: 0.00 AC: 0 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5192

South Asian (SAS) AF: 0.00 AC: 0 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10602

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68010

Other (OTH) AF: 0.00 AC: 0 AN: 2090

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.00000037155), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.0000215 Hom.: 0

Bravo AF: 0.0000151

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.60
CADD	Benign	0.34
DANN	Benign	0.69
PhyloP100		-3.6
Mutation Taster		=78/22	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.050
dbscSNV1_RF	Benign	0.39
SpliceAI score (max)		0.060		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: rs768161152; hg19: chr1-237949334; COSMIC: COSV63699041;