rs376788358

Variant names:

• chr1-237659982-A-G
• rs376788358
• NM_001035.3:c.8209-3A>G

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_001035.3(RYR2):​c.8209-3A>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 0.0000745 in 1,571,196 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. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00043 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000036 (0 hom.)
• Consequence: RYR2 NM_001035.3 splice_region, intron
• Scores: Splicing: ADA: 0.02390
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:6
• Conservation: PhyloP100: -0.396
• 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: ClinGen, G2P, Orphanet
• 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 1-237659982-A-G is Benign according to our data. Variant chr1-237659982-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 43829.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.000434 (66/152196) while in subpopulation AFR AF = 0.00156 (65/41560). AF 95% confidence interval is 0.00126. There are 0 homozygotes in GnomAd4. There are 23 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 66 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.8209-3A>G		splice_region intron	N/A	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.8209-3A>G		splice_region intron	N/A	ENSP00000355533.2	Q92736-1
	RYR2	ENST00000661330.2		c.8209-3A>G		splice_region intron	N/A	ENSP00000499393.2	A0A590UJF6
	RYR2	ENST00000609119.2	TSL:5	n.8209-3A>G		splice_region intron	N/A	ENSP00000499659.2	A0A590UK06

Frequencies

GnomAD3 genomes AF: 0.000434 AC: 66 AN: 152078 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00157

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000902 AC: 19 AN: 210540 AF XY: 0.0000610

Gnomad AFR exome AF: 0.00138

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: 0.00000993

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000359 AC: 51 AN: 1419000 Hom.: 0 Cov.: 28 AF XY: 0.0000284 AC XY: 20 AN XY: 704906

African (AFR) AF: 0.00136 AC: 42 AN: 30994

American (AMR) AF: 0.0000565 AC: 2 AN: 35402

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25014

East Asian (EAS) AF: 0.00 AC: 0 AN: 37938

South Asian (SAS) AF: 0.00 AC: 0 AN: 76774

European-Finnish (FIN) AF: 0.0000189 AC: 1 AN: 52792

Middle Eastern (MID) AF: 0.000176 AC: 1 AN: 5680

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1095804

Other (OTH) AF: 0.0000853 AC: 5 AN: 58602

GnomAD4 genome AF: 0.000434 AC: 66 AN: 152196 Hom.: 0 Cov.: 33 AF XY: 0.000309 AC XY: 23 AN XY: 74390

African (AFR) AF: 0.00156 AC: 65 AN: 41560

American (AMR) AF: 0.0000654 AC: 1 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10580

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67994

Other (OTH) AF: 0.00 AC: 0 AN: 2106

Alfa AF: 0.000561 Hom.: 0

Bravo AF: 0.000446

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	2	not specified (2)
-	-	1	Cardiomyopathy (1)
-	-	1	Cardiovascular phenotype (1)
-	-	1	Catecholaminergic polymorphic ventricular tachycardia 1 (1)
-	1	-	Dilated cardiomyopathy with left ventricular noncompaction (1)
-	1	-	not provided (1)
-	-	1	RYR2-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	5.7
DANN	Benign	0.45
PhyloP100		-0.40

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.024
dbscSNV1_RF	Benign	0.44
SpliceAI score (max)		0.17		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: rs376788358; hg19: chr1-237823282;