NM_001035.3:c.4684-6C>G

Variant names:

• chr1-237610756-C-G
• rs755712032
• NM_001035.3:c.4684-6C>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001035.3(RYR2):​c.4684-6C>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000209 in 1,438,078 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: RYR2 NM_001035.3 splice_region, intron
• Scores: Splicing: ADA: 0.006795
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0460
• 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RYR2	NM_001035.3	MANE Select	c.4684-6C>G		splice_region intron	N/A	NP_001026.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RYR2	ENST00000366574.7	TSL:1 MANE Select	c.4684-6C>G		splice_region intron	N/A	ENSP00000355533.2
	RYR2	ENST00000661330.2		c.4684-6C>G		splice_region intron	N/A	ENSP00000499393.2
	RYR2	ENST00000609119.2	TSL:5	n.4684-6C>G		splice_region intron	N/A	ENSP00000499659.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000449 AC: 1 AN: 222908 AF XY: 0.00000833

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000209 AC: 3 AN: 1438078 Hom.: 0 Cov.: 30 AF XY: 0.00000281 AC XY: 2 AN XY: 712586

African (AFR) AF: 0.00 AC: 0 AN: 33018

American (AMR) AF: 0.00 AC: 0 AN: 41616

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25612

East Asian (EAS) AF: 0.00 AC: 0 AN: 38842

South Asian (SAS) AF: 0.0000240 AC: 2 AN: 83226

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52454

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4468

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1099386

Other (OTH) AF: 0.0000168 AC: 1 AN: 59456

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	3.5
DANN	Benign	0.47
PhyloP100		-0.046

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0068
dbscSNV1_RF	Benign	0.33
SpliceAI score (max)		0.11		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: rs755712032; hg19: chr1-237774056;