rs41305973

chr1-237635042-G-Achr1-237635042-G-Cchr1-237635042-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001035.3(RYR2):c.6792+50G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.103 in 1,299,190 control chromosomes in the GnomAD database, including 8,224 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.076 (597 hom., cov: 32)
  • Exomes 𝑓: 0.11 (7627 hom.)
• Consequence: RYR2 NM_001035.3 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.369

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.93).
• BP6: Variant 1-237635042-G-A is Benign according to our data. Variant chr1-237635042-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 257215.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.115 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RYR2	NM_001035.3	c.6792+50G>A		intron_variant		ENST00000366574.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RYR2	ENST00000366574.7	c.6792+50G>A		intron_variant		1	NM_001035.3	P1
RYR2	ENST00000659194.3	c.6792+50G>A		intron_variant
RYR2	ENST00000660292.2	c.6792+50G>A		intron_variant
RYR2	ENST00000609119.2	c.6792+50G>A		intron_variant, NMD_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.0758 AC: 11517 AN: 152000 Hom.: 597 Cov.: 32

Gnomad AFR AF: 0.0214

Gnomad AMI AF: 0.0833

Gnomad AMR AF: 0.0578

Gnomad ASJ AF: 0.0458

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.0110

Gnomad FIN AF: 0.127

Gnomad MID AF: 0.0348

Gnomad NFE AF: 0.117

Gnomad OTH AF: 0.0686

GnomAD3 exomes AF: 0.0798 AC: 8373 AN: 104924 Hom.: 485 AF XY: 0.0784 AC XY: 4338 AN XY: 55300

Gnomad AFR exome AF: 0.0183

Gnomad AMR exome AF: 0.0444

Gnomad ASJ exome AF: 0.0422

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0134

Gnomad FIN exome AF: 0.134

Gnomad NFE exome AF: 0.113

Gnomad OTH exome AF: 0.0828

GnomAD4 exome AF: 0.107 AC: 122304 AN: 1147072 Hom.: 7627 Cov.: 14 AF XY: 0.104 AC XY: 58473 AN XY: 560870

Gnomad4 AFR exome AF: 0.0159

Gnomad4 AMR exome AF: 0.0470

Gnomad4 ASJ exome AF: 0.0396

Gnomad4 EAS exome AF: 0.000122

Gnomad4 SAS exome AF: 0.0129

Gnomad4 FIN exome AF: 0.134

Gnomad4 NFE exome AF: 0.121

Gnomad4 OTH exome AF: 0.0873

GnomAD4 genome AF: 0.0757 AC: 11516 AN: 152118 Hom.: 597 Cov.: 32 AF XY: 0.0747 AC XY: 5555 AN XY: 74376

Gnomad4 AFR AF: 0.0214

Gnomad4 AMR AF: 0.0578

Gnomad4 ASJ AF: 0.0458

Gnomad4 EAS AF: 0.000386

Gnomad4 SAS AF: 0.0110

Gnomad4 FIN AF: 0.127

Gnomad4 NFE AF: 0.117

Gnomad4 OTH AF: 0.0679

Alfa AF: 0.0721 Hom.: 179

Bravo AF: 0.0686

Asia WGS AF: 0.00837 AC: 30 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

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- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 26, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
Cadd	Benign	0.41
Dann	Benign	0.77

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

Publications

LitVar

Other links and lift over

dbSNP: rs41305973; hg19: chr1-237798342;