chr1-237633537-G-A

Variant names:

• chr1-237633537-G-A
• rs10802626
• NM_001035.3:c.6556-41G>A

Variant summary

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

The ENST00000366574.7(RYR2):​c.6556-41G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.354 in 1,610,230 control chromosomes in the GnomAD database, including 102,991 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.40 (12271 hom., cov: 32)
  • Exomes 𝑓: 0.35 (90720 hom.)
• Consequence: RYR2 ENST00000366574.7 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.235
• Publications: 10 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=-0.92).
• BP6: Variant 1-237633537-G-A is Benign according to our data. Variant chr1-237633537-G-A is described in ClinVar as Benign. ClinVar VariationId is 257214.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.499 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000366574.7. 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.6556-41G>A		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.6556-41G>A		intron	N/A	ENSP00000355533.2
	RYR2	ENST00000661330.2		c.6556-41G>A		intron	N/A	ENSP00000499393.2
	RYR2	ENST00000609119.2	TSL:5	n.6556-41G>A		intron	N/A	ENSP00000499659.2

Frequencies

GnomAD3 genomes AF: 0.395 AC: 59993 AN: 151868 Hom.: 12238 Cov.: 32

Gnomad AFR AF: 0.504

Gnomad AMI AF: 0.412

Gnomad AMR AF: 0.400

Gnomad ASJ AF: 0.215

Gnomad EAS AF: 0.459

Gnomad SAS AF: 0.362

Gnomad FIN AF: 0.358

Gnomad MID AF: 0.285

Gnomad NFE AF: 0.341

Gnomad OTH AF: 0.369

GnomAD2 exomes AF: 0.362 AC: 89803 AN: 248406 AF XY: 0.356

Gnomad AFR exome AF: 0.513

Gnomad AMR exome AF: 0.391

Gnomad ASJ exome AF: 0.208

Gnomad EAS exome AF: 0.465

Gnomad FIN exome AF: 0.365

Gnomad NFE exome AF: 0.336

Gnomad OTH exome AF: 0.340

GnomAD4 exome AF: 0.350 AC: 509664 AN: 1458244 Hom.: 90720 Cov.: 31 AF XY: 0.349 AC XY: 252758 AN XY: 725216

African (AFR) AF: 0.507 AC: 16926 AN: 33368

American (AMR) AF: 0.396 AC: 17656 AN: 44602

Ashkenazi Jewish (ASJ) AF: 0.210 AC: 5474 AN: 26054

East Asian (EAS) AF: 0.431 AC: 17096 AN: 39628

South Asian (SAS) AF: 0.349 AC: 30008 AN: 86078

European-Finnish (FIN) AF: 0.358 AC: 19094 AN: 53288

Middle Eastern (MID) AF: 0.284 AC: 1635 AN: 5766

European-Non Finnish (NFE) AF: 0.343 AC: 380589 AN: 1109220

Other (OTH) AF: 0.352 AC: 21186 AN: 60240

GnomAD4 genome AF: 0.395 AC: 60080 AN: 151986 Hom.: 12271 Cov.: 32 AF XY: 0.393 AC XY: 29220 AN XY: 74276

African (AFR) AF: 0.505 AC: 20937 AN: 41466

American (AMR) AF: 0.400 AC: 6107 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.215 AC: 746 AN: 3464

East Asian (EAS) AF: 0.459 AC: 2367 AN: 5158

South Asian (SAS) AF: 0.362 AC: 1736 AN: 4800

European-Finnish (FIN) AF: 0.358 AC: 3780 AN: 10544

Middle Eastern (MID) AF: 0.286 AC: 84 AN: 294

European-Non Finnish (NFE) AF: 0.341 AC: 23165 AN: 67972

Other (OTH) AF: 0.373 AC: 784 AN: 2104

Alfa AF: 0.348 Hom.: 14371

Bravo AF: 0.405

Asia WGS AF: 0.457 AC: 1588 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Arrhythmogenic right ventricular dysplasia 2 (1)
-	-	1	Cardiac arrhythmia (1)
-	-	1	Catecholaminergic polymorphic ventricular tachycardia 1 (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	1.8
DANN	Benign	0.55
PhyloP100		0.23
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: rs10802626; hg19: chr1-237796837; COSMIC: COSV63687186;