1-237042502-C-G

Variant names:

• chr1-237042502-C-G
• rs778527185
• NM_001035.3:c.-20C>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The NM_001035.3(RYR2):​c.-20C>G variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000109 in 1,096,182 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000011 (0 hom.)
• Consequence: RYR2 NM_001035.3 5_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.946
• 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: Ambry Genetics, Laboratory for Molecular Medicine
• catecholaminergic polymorphic ventricular tachycardia

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: G2P, ClinGen, Orphanet
• catecholaminergic polymorphic ventricular tachycardia 1

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.55).
• BS1: Variant frequency is greater than expected in population eas. GnomAdExome4 allele frequency = 0.0000109 (12/1096182) while in subpopulation EAS AF = 0.000451 (12/26604). AF 95% confidence interval is 0.00026. There are 0 homozygotes in GnomAdExome4. There are 5 alleles in the male GnomAdExome4 subpopulation. Median coverage is 30. This position passed quality control check.
• BS2: High AC in GnomAdExome4 at 12 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.-20C>G		5_prime_UTR	Exon 1 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.-20C>G		5_prime_UTR	Exon 1 of 105	ENSP00000355533.2	Q92736-1
	RYR2	ENST00000661330.2		c.-20C>G		5_prime_UTR	Exon 1 of 106	ENSP00000499393.2	A0A590UJF6
	RYR2	ENST00000609119.2	TSL:5	n.-20C>G		non_coding_transcript_exon	Exon 1 of 104	ENSP00000499659.2	A0A590UK06

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.0000109 AC: 12 AN: 1096182 Hom.: 0 Cov.: 30 AF XY: 0.00000965 AC XY: 5 AN XY: 517954

African (AFR) AF: 0.00 AC: 0 AN: 23072

American (AMR) AF: 0.00 AC: 0 AN: 8478

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 14280

East Asian (EAS) AF: 0.000451 AC: 12 AN: 26604

South Asian (SAS) AF: 0.00 AC: 0 AN: 19670

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 35920

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4328

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 919990

Other (OTH) AF: 0.00 AC: 0 AN: 43840

GnomAD4 genome Cov.: 33

Asia WGS AF: 0.000289 AC: 1 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.55
CADD	Benign	14
DANN	Benign	0.90
PhyloP100		0.95
PromoterAI		-0.011	Neutral

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: rs778527185; hg19: chr1-237205802;