rs186326951

Variant names:

• chr1-237711740-C-T
• rs186326951
• NM_001035.3:c.10231-5C>T

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.10231-5C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000334 in 1,533,892 control chromosomes in the GnomAD database, including 3 homozygotes. 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 0.00029 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00034 (3 hom.)
• Consequence: RYR2 NM_001035.3 splice_region, intron
• Scores: Splicing: ADA: 0.0001899
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:13
• Conservation: PhyloP100: 0.967
• Publications: 1 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=-0.49).
• BP6: Variant 1-237711740-C-T is Benign according to our data. Variant chr1-237711740-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 138954.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.000289 (44/152242) while in subpopulation AMR AF = 0.000589 (9/15292). AF 95% confidence interval is 0.000307. There are 0 homozygotes in GnomAd4. There are 22 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 44 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.10231-5C>T		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.10231-5C>T		splice_region intron	N/A	ENSP00000355533.2	Q92736-1
	RYR2	ENST00000661330.2		c.10231-5C>T		splice_region intron	N/A	ENSP00000499393.2	A0A590UJF6
	RYR2	ENST00000609119.2	TSL:5	n.*1266-5C>T		splice_region intron	N/A	ENSP00000499659.2	A0A590UK06

Frequencies

GnomAD3 genomes AF: 0.000289 AC: 44 AN: 152124 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000589

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000660

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000368

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000543 AC: 123 AN: 226606 AF XY: 0.000556

Gnomad AFR exome AF: 0.0000732

Gnomad AMR exome AF: 0.000594

Gnomad ASJ exome AF: 0.000214

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000917

Gnomad NFE exome AF: 0.000700

Gnomad OTH exome AF: 0.00124

GnomAD4 exome AF: 0.000339 AC: 468 AN: 1381650 Hom.: 3 Cov.: 23 AF XY: 0.000336 AC XY: 232 AN XY: 689556

African (AFR) AF: 0.0000626 AC: 2 AN: 31962

American (AMR) AF: 0.000612 AC: 26 AN: 42518

Ashkenazi Jewish (ASJ) AF: 0.000159 AC: 4 AN: 25222

East Asian (EAS) AF: 0.00 AC: 0 AN: 39166

South Asian (SAS) AF: 0.000159 AC: 13 AN: 81536

European-Finnish (FIN) AF: 0.00116 AC: 61 AN: 52598

Middle Eastern (MID) AF: 0.00387 AC: 21 AN: 5426

European-Non Finnish (NFE) AF: 0.000304 AC: 318 AN: 1045754

Other (OTH) AF: 0.000400 AC: 23 AN: 57468

GnomAD4 genome AF: 0.000289 AC: 44 AN: 152242 Hom.: 0 Cov.: 32 AF XY: 0.000296 AC XY: 22 AN XY: 74438

African (AFR) AF: 0.0000722 AC: 3 AN: 41530

American (AMR) AF: 0.000589 AC: 9 AN: 15292

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.000660 AC: 7 AN: 10612

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

European-Non Finnish (NFE) AF: 0.000368 AC: 25 AN: 68014

Other (OTH) AF: 0.00 AC: 0 AN: 2116

Alfa AF: 0.000563 Hom.: 0

Bravo AF: 0.000385

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	4	not provided (4)
-	-	2	Catecholaminergic polymorphic ventricular tachycardia 1 (2)
-	1	-	Arrhythmogenic right ventricular dysplasia 2 (1)
-	-	1	Cardiomyopathy (1)
-	-	1	Cardiovascular phenotype (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.49
CADD	Benign	12
DANN	Benign	0.72
PhyloP100		0.97
Mutation Taster		=83/17	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00019
dbscSNV1_RF	Benign	0.068
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: rs186326951; hg19: chr1-237875040;