NM_001035.3:c.2204-7C>G

Variant names:

• chr1-237500704-C-G
• rs147479514
• NM_001035.3:c.2204-7C>G

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.2204-7C>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 0.011 in 1,589,644 control chromosomes in the GnomAD database, including 136 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 Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0091 (12 hom., cov: 32)
  • Exomes 𝑓: 0.011 (124 hom.)
• Consequence: RYR2 NM_001035.3 splice_region, intron
• Scores: Splicing: ADA: 0.003871
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:19
• Conservation: PhyloP100: -0.0540
• Publications: 2 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=-0.79).
• BP6: Variant 1-237500704-C-G is Benign according to our data. Variant chr1-237500704-C-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 36738.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 = 0.00914 (1391/152250) while in subpopulation NFE AF = 0.0132 (896/67996). AF 95% confidence interval is 0.0125. There are 12 homozygotes in GnomAd4. There are 717 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1391 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.2204-7C>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.2204-7C>G		splice_region intron	N/A	ENSP00000355533.2	Q92736-1
	RYR2	ENST00000661330.2		c.2204-7C>G		splice_region intron	N/A	ENSP00000499393.2	A0A590UJF6
	RYR2	ENST00000609119.2	TSL:5	n.2204-7C>G		splice_region intron	N/A	ENSP00000499659.2	A0A590UK06

Frequencies

GnomAD3 genomes AF: 0.00914 AC: 1391 AN: 152132 Hom.: 12 Cov.: 32

Gnomad AFR AF: 0.00159

Gnomad AMI AF: 0.0482

Gnomad AMR AF: 0.00426

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00331

Gnomad FIN AF: 0.0274

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0132

Gnomad OTH AF: 0.00525

GnomAD2 exomes AF: 0.00959 AC: 2307 AN: 240644 AF XY: 0.00962

Gnomad AFR exome AF: 0.00170

Gnomad AMR exome AF: 0.00373

Gnomad ASJ exome AF: 0.000107

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0273

Gnomad NFE exome AF: 0.0123

Gnomad OTH exome AF: 0.0133

GnomAD4 exome AF: 0.0112 AC: 16137 AN: 1437394 Hom.: 124 Cov.: 31 AF XY: 0.0110 AC XY: 7847 AN XY: 711204

African (AFR) AF: 0.00116 AC: 38 AN: 32772

American (AMR) AF: 0.00387 AC: 166 AN: 42948

Ashkenazi Jewish (ASJ) AF: 0.000277 AC: 7 AN: 25272

East Asian (EAS) AF: 0.0000509 AC: 2 AN: 39290

South Asian (SAS) AF: 0.00563 AC: 468 AN: 83174

European-Finnish (FIN) AF: 0.0281 AC: 1486 AN: 52888

Middle Eastern (MID) AF: 0.00603 AC: 34 AN: 5642

European-Non Finnish (NFE) AF: 0.0121 AC: 13294 AN: 1096226

Other (OTH) AF: 0.0108 AC: 642 AN: 59182

GnomAD4 genome AF: 0.00914 AC: 1391 AN: 152250 Hom.: 12 Cov.: 32 AF XY: 0.00963 AC XY: 717 AN XY: 74458

African (AFR) AF: 0.00159 AC: 66 AN: 41558

American (AMR) AF: 0.00425 AC: 65 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5182

South Asian (SAS) AF: 0.00332 AC: 16 AN: 4826

European-Finnish (FIN) AF: 0.0274 AC: 290 AN: 10598

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0132 AC: 896 AN: 67996

Other (OTH) AF: 0.00520 AC: 11 AN: 2116

Alfa AF: 0.0115 Hom.: 4

Bravo AF: 0.00734

Asia WGS AF: 0.00202 AC: 7 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not provided (6)
-	-	5	not specified (5)
-	-	3	Cardiomyopathy (3)
-	-	2	Catecholaminergic polymorphic ventricular tachycardia 1 (2)
-	-	1	Arrhythmogenic right ventricular dysplasia 2 (1)
-	-	1	Cardiovascular phenotype (1)
-	-	1	Catecholaminergic polymorphic ventricular tachycardia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	2.4
DANN	Benign	0.60
PhyloP100		-0.054
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0039
dbscSNV1_RF	Benign	0.10
SpliceAI score (max)		0.010		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: rs147479514; hg19: chr1-237664004;