NM_001035.3:c.3214+112G>A

Variant names:

• chr1-237550803-G-A
• rs2306238
• NM_001035.3:c.3214+112G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001035.3(RYR2):​c.3214+112G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.208 in 1,178,198 control chromosomes in the GnomAD database, including 26,982 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.19 (2961 hom., cov: 32)
  • Exomes 𝑓: 0.21 (24021 hom.)
• Consequence: RYR2 NM_001035.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.386
• Publications: 13 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=-0.88).
• BP6: Variant 1-237550803-G-A is Benign according to our data. Variant chr1-237550803-G-A is described in ClinVar as Benign. ClinVar VariationId is 672392.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.274 is higher than 0.05.

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.3214+112G>A		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.3214+112G>A		intron	N/A	ENSP00000355533.2	Q92736-1
	RYR2	ENST00000661330.2		c.3214+112G>A		intron	N/A	ENSP00000499393.2	A0A590UJF6
	RYR2	ENST00000609119.2	TSL:5	n.3214+112G>A		intron	N/A	ENSP00000499659.2	A0A590UK06

Frequencies

GnomAD3 genomes AF: 0.186 AC: 28310 AN: 152024 Hom.: 2956 Cov.: 32

Gnomad AFR AF: 0.0807

Gnomad AMI AF: 0.231

Gnomad AMR AF: 0.281

Gnomad ASJ AF: 0.263

Gnomad EAS AF: 0.256

Gnomad SAS AF: 0.285

Gnomad FIN AF: 0.186

Gnomad MID AF: 0.226

Gnomad NFE AF: 0.211

Gnomad OTH AF: 0.232

GnomAD4 exome AF: 0.211 AC: 216535 AN: 1026054 Hom.: 24021 AF XY: 0.214 AC XY: 107224 AN XY: 502146

African (AFR) AF: 0.0698 AC: 1599 AN: 22918

American (AMR) AF: 0.302 AC: 5161 AN: 17096

Ashkenazi Jewish (ASJ) AF: 0.252 AC: 4049 AN: 16096

East Asian (EAS) AF: 0.289 AC: 9303 AN: 32140

South Asian (SAS) AF: 0.265 AC: 11911 AN: 45024

European-Finnish (FIN) AF: 0.179 AC: 7430 AN: 41538

Middle Eastern (MID) AF: 0.229 AC: 696 AN: 3034

European-Non Finnish (NFE) AF: 0.208 AC: 166912 AN: 804218

Other (OTH) AF: 0.215 AC: 9474 AN: 43990

GnomAD4 genome AF: 0.186 AC: 28322 AN: 152144 Hom.: 2961 Cov.: 32 AF XY: 0.190 AC XY: 14129 AN XY: 74366

African (AFR) AF: 0.0805 AC: 3343 AN: 41530

American (AMR) AF: 0.281 AC: 4295 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.263 AC: 914 AN: 3470

East Asian (EAS) AF: 0.256 AC: 1323 AN: 5176

South Asian (SAS) AF: 0.287 AC: 1382 AN: 4818

European-Finnish (FIN) AF: 0.186 AC: 1963 AN: 10582

Middle Eastern (MID) AF: 0.223 AC: 65 AN: 292

European-Non Finnish (NFE) AF: 0.211 AC: 14340 AN: 67978

Other (OTH) AF: 0.230 AC: 486 AN: 2114

Alfa AF: 0.212 Hom.: 6090

Bravo AF: 0.191

Asia WGS AF: 0.244 AC: 851 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.96
DANN	Benign	0.65
PhyloP100		-0.39
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: rs2306238; hg19: chr1-237714103; COSMIC: COSV63672640; COSMIC: COSV63672640;