chr1-237709587-T-C

Variant names:

• chr1-237709587-T-C
• rs74323916
• NM_001035.3:c.10230+20T>C

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.10230+20T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0139 in 1,519,598 control chromosomes in the GnomAD database, including 179 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.011 (19 hom., cov: 32)
  • Exomes 𝑓: 0.014 (160 hom.)
• Consequence: RYR2 NM_001035.3 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -0.618
• Publications: 4 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 1-237709587-T-C is Benign according to our data. Variant chr1-237709587-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 36728.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.0114 (1736/152212) while in subpopulation AMR AF = 0.0157 (240/15292). AF 95% confidence interval is 0.0141. There are 19 homozygotes in GnomAd4. There are 800 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1736 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RYR2	NM_001035.3	MANE Select	c.10230+20T>C		intron	N/A	NP_001026.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RYR2	ENST00000366574.7	TSL:1 MANE Select	c.10230+20T>C		intron	N/A	ENSP00000355533.2
	RYR2	ENST00000661330.2		c.10230+20T>C		intron	N/A	ENSP00000499393.2
	RYR2	ENST00000609119.2	TSL:5	n.*1265+20T>C		intron	N/A	ENSP00000499659.2

Frequencies

GnomAD3 genomes AF: 0.0114 AC: 1731 AN: 152094 Hom.: 18 Cov.: 32

Gnomad AFR AF: 0.00616

Gnomad AMI AF: 0.0713

Gnomad AMR AF: 0.0158

Gnomad ASJ AF: 0.00922

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0137

Gnomad FIN AF: 0.00236

Gnomad MID AF: 0.0191

Gnomad NFE AF: 0.0148

Gnomad OTH AF: 0.0172

GnomAD2 exomes AF: 0.0112 AC: 2493 AN: 222208 AF XY: 0.0119

Gnomad AFR exome AF: 0.00464

Gnomad AMR exome AF: 0.00866

Gnomad ASJ exome AF: 0.00974

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00271

Gnomad NFE exome AF: 0.0153

Gnomad OTH exome AF: 0.0139

GnomAD4 exome AF: 0.0142 AC: 19426 AN: 1367386 Hom.: 160 Cov.: 20 AF XY: 0.0143 AC XY: 9746 AN XY: 683224

African (AFR) AF: 0.00567 AC: 179 AN: 31562

American (AMR) AF: 0.00844 AC: 356 AN: 42178

Ashkenazi Jewish (ASJ) AF: 0.00824 AC: 207 AN: 25136

East Asian (EAS) AF: 0.0000514 AC: 2 AN: 38908

South Asian (SAS) AF: 0.0144 AC: 1168 AN: 81098

European-Finnish (FIN) AF: 0.00327 AC: 172 AN: 52570

Middle Eastern (MID) AF: 0.0221 AC: 123 AN: 5578

European-Non Finnish (NFE) AF: 0.0160 AC: 16544 AN: 1033222

Other (OTH) AF: 0.0118 AC: 675 AN: 57134

GnomAD4 genome AF: 0.0114 AC: 1736 AN: 152212 Hom.: 19 Cov.: 32 AF XY: 0.0107 AC XY: 800 AN XY: 74426

African (AFR) AF: 0.00626 AC: 260 AN: 41538

American (AMR) AF: 0.0157 AC: 240 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00922 AC: 32 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5166

South Asian (SAS) AF: 0.0135 AC: 65 AN: 4820

European-Finnish (FIN) AF: 0.00236 AC: 25 AN: 10602

Middle Eastern (MID) AF: 0.0205 AC: 6 AN: 292

European-Non Finnish (NFE) AF: 0.0148 AC: 1007 AN: 68006

Other (OTH) AF: 0.0170 AC: 36 AN: 2114

Alfa AF: 0.0118 Hom.: 8

Bravo AF: 0.0115

Asia WGS AF: 0.00520 AC: 18 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	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	-0.85
CADD	Benign	1.3
DANN	Benign	0.39
PhyloP100		-0.62
PromoterAI		0.025	Neutral
Mutation Taster		=100/0	polymorphism

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: rs74323916; hg19: chr1-237872887;