rs113408406

Variant names:

• chr1-237770906-C-T
• rs113408406
• NM_001035.3:c.11557+19C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001035.3(RYR2):​c.11557+19C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0255 in 1,475,274 control chromosomes in the GnomAD database, including 620 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.019 (46 hom., cov: 32)
  • Exomes 𝑓: 0.026 (574 hom.)
• Consequence: RYR2 NM_001035.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: -1.88
• Publications: 3 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 1-237770906-C-T is Benign according to our data. Variant chr1-237770906-C-T is described in ClinVar as Benign. ClinVar VariationId is 36731.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.019 (2889/152272) while in subpopulation NFE AF = 0.0292 (1986/68026). AF 95% confidence interval is 0.0281. There are 46 homozygotes in GnomAd4. There are 1459 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 2889 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.11557+19C>T		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.11557+19C>T		intron	N/A	ENSP00000355533.2	Q92736-1
	RYR2	ENST00000661330.2		c.11581+19C>T		intron	N/A	ENSP00000499393.2	A0A590UJF6
	RYR2	ENST00000609119.2	TSL:5	n.*2649+19C>T		intron	N/A	ENSP00000499659.2	A0A590UK06

Frequencies

GnomAD3 genomes AF: 0.0190 AC: 2891 AN: 152154 Hom.: 46 Cov.: 32

Gnomad AFR AF: 0.00519

Gnomad AMI AF: 0.0702

Gnomad AMR AF: 0.00858

Gnomad ASJ AF: 0.00259

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00166

Gnomad FIN AF: 0.0427

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0292

Gnomad OTH AF: 0.0110

GnomAD2 exomes AF: 0.0178 AC: 2709 AN: 151872 AF XY: 0.0173

Gnomad AFR exome AF: 0.00415

Gnomad AMR exome AF: 0.00660

Gnomad ASJ exome AF: 0.00245

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0439

Gnomad NFE exome AF: 0.0285

Gnomad OTH exome AF: 0.0144

GnomAD4 exome AF: 0.0262 AC: 34667 AN: 1323002 Hom.: 574 Cov.: 20 AF XY: 0.0254 AC XY: 16643 AN XY: 654568

African (AFR) AF: 0.00375 AC: 113 AN: 30104

American (AMR) AF: 0.00633 AC: 220 AN: 34754

Ashkenazi Jewish (ASJ) AF: 0.00226 AC: 55 AN: 24284

East Asian (EAS) AF: 0.00 AC: 0 AN: 35116

South Asian (SAS) AF: 0.00177 AC: 135 AN: 76342

European-Finnish (FIN) AF: 0.0417 AC: 2036 AN: 48812

Middle Eastern (MID) AF: 0.00183 AC: 10 AN: 5470

European-Non Finnish (NFE) AF: 0.0306 AC: 31037 AN: 1012992

Other (OTH) AF: 0.0192 AC: 1061 AN: 55128

GnomAD4 genome AF: 0.0190 AC: 2889 AN: 152272 Hom.: 46 Cov.: 32 AF XY: 0.0196 AC XY: 1459 AN XY: 74454

African (AFR) AF: 0.00517 AC: 215 AN: 41562

American (AMR) AF: 0.00857 AC: 131 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00259 AC: 9 AN: 3470

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

South Asian (SAS) AF: 0.00166 AC: 8 AN: 4822

European-Finnish (FIN) AF: 0.0427 AC: 453 AN: 10606

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

European-Non Finnish (NFE) AF: 0.0292 AC: 1986 AN: 68026

Other (OTH) AF: 0.0109 AC: 23 AN: 2110

Alfa AF: 0.0255 Hom.: 94

Bravo AF: 0.0164

Asia WGS AF: 0.00173 AC: 6 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	7	not specified (7)
-	-	4	not provided (4)
-	-	1	Catecholaminergic polymorphic ventricular tachycardia 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.080
DANN	Benign	0.29
PhyloP100		-1.9
Mutation Taster		=100/0	polymorphism (auto)

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: rs113408406; hg19: chr1-237934206;