1-237711741-T-C

Variant names:

• chr1-237711741-T-C
• rs117180147
• NM_001035.3:c.10231-4T>C

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.10231-4T>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000267 in 1,538,886 control chromosomes in the GnomAD database, including 6 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 0.00060 (4 hom., cov: 32)
  • Exomes 𝑓: 0.00023 (2 hom.)
• Consequence: RYR2 NM_001035.3 splice_region, intron
• Scores: Splicing: ADA: 0.0004187
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:15
• Conservation: PhyloP100: -0.0530
• Publications: 5 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: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.62).
• BP6: Variant 1-237711741-T-C is Benign according to our data. Variant chr1-237711741-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 167631.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.000604 (92/152318) while in subpopulation EAS AF = 0.00945 (49/5184). AF 95% confidence interval is 0.00735. There are 4 homozygotes in GnomAd4. There are 24 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 92 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.10231-4T>C		splice_region intron	N/A	NP_001026.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RYR2	ENST00000366574.7	TSL:1 MANE Select	c.10231-4T>C		splice_region intron	N/A	ENSP00000355533.2
	RYR2	ENST00000661330.2		c.10231-4T>C		splice_region intron	N/A	ENSP00000499393.2
	RYR2	ENST00000609119.2	TSL:5	n.*1266-4T>C		splice_region intron	N/A	ENSP00000499659.2

Frequencies

GnomAD3 genomes AF: 0.000604 AC: 92 AN: 152200 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.000145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00203

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00943

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00191

GnomAD2 exomes AF: 0.000726 AC: 165 AN: 227240 AF XY: 0.000620

Gnomad AFR exome AF: 0.000511

Gnomad AMR exome AF: 0.0000624

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00899

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000709

GnomAD4 exome AF: 0.000230 AC: 319 AN: 1386568 Hom.: 2 Cov.: 23 AF XY: 0.000224 AC XY: 155 AN XY: 691794

African (AFR) AF: 0.000156 AC: 5 AN: 32042

American (AMR) AF: 0.0000469 AC: 2 AN: 42660

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25264

East Asian (EAS) AF: 0.00518 AC: 203 AN: 39192

South Asian (SAS) AF: 0.0000245 AC: 2 AN: 81710

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52632

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5432

European-Non Finnish (NFE) AF: 0.00000381 AC: 4 AN: 1049982

Other (OTH) AF: 0.00179 AC: 103 AN: 57654

GnomAD4 genome AF: 0.000604 AC: 92 AN: 152318 Hom.: 4 Cov.: 32 AF XY: 0.000322 AC XY: 24 AN XY: 74494

African (AFR) AF: 0.000144 AC: 6 AN: 41574

American (AMR) AF: 0.00203 AC: 31 AN: 15300

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

East Asian (EAS) AF: 0.00945 AC: 49 AN: 5184

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

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

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68018

Other (OTH) AF: 0.00189 AC: 4 AN: 2114

Alfa AF: 0.000206 Hom.: 0

Bravo AF: 0.000472

Asia WGS AF: 0.00751 AC: 26 AN: 3476

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	6	not provided (7)
-	1	3	not specified (4)
-	-	2	Cardiomyopathy (2)
-	-	2	Catecholaminergic polymorphic ventricular tachycardia 1 (2)
-	-	1	Arrhythmogenic right ventricular dysplasia 2 (1)
-	-	1	Cardiovascular phenotype (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.62
CADD	Benign	11
DANN	Benign	0.80
PhyloP100		-0.053
Mutation Taster		=94/6	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00042
dbscSNV1_RF	Benign	0.054
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: rs117180147; hg19: chr1-237875041;