rs2056387

Positions:

• chr1-237760812-C-A
• chr1-237760812-C-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.11403-143C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.31 in 557,426 control chromosomes in the GnomAD database, including 26,840 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.33 (7618 hom., cov: 31)
  • Exomes 𝑓: 0.30 (19222 hom.)
• Consequence: RYR2 NM_001035.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.415

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=-0.78).
• BP6: Variant 1-237760812-C-A is Benign according to our data. Variant chr1-237760812-C-A is described in ClinVar as [Benign]. Clinvar id is 671779.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.355 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RYR2	NM_001035.3	c.11403-143C>A		intron_variant		ENST00000366574.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RYR2	ENST00000366574.7	c.11403-143C>A		intron_variant		1	NM_001035.3	P1
RYR2	ENST00000659194.3	c.11391-143C>A		intron_variant
RYR2	ENST00000660292.2	c.11391-143C>A		intron_variant
RYR2	ENST00000609119.2	c.*2495-143C>A		intron_variant, NMD_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.335 AC: 47595 AN: 142060 Hom.: 7617 Cov.: 31

Gnomad AFR AF: 0.360

Gnomad AMI AF: 0.393

Gnomad AMR AF: 0.355

Gnomad ASJ AF: 0.303

Gnomad EAS AF: 0.0396

Gnomad SAS AF: 0.198

Gnomad FIN AF: 0.384

Gnomad MID AF: 0.368

Gnomad NFE AF: 0.341

Gnomad OTH AF: 0.343

GnomAD4 exome AF: 0.302 AC: 125237 AN: 415246 Hom.: 19222 AF XY: 0.294 AC XY: 65370 AN XY: 222466

Gnomad4 AFR exome AF: 0.349

Gnomad4 AMR exome AF: 0.342

Gnomad4 ASJ exome AF: 0.283

Gnomad4 EAS exome AF: 0.0431

Gnomad4 SAS exome AF: 0.192

Gnomad4 FIN exome AF: 0.372

Gnomad4 NFE exome AF: 0.336

Gnomad4 OTH exome AF: 0.309

GnomAD4 genome AF: 0.335 AC: 47620 AN: 142180 Hom.: 7618 Cov.: 31 AF XY: 0.332 AC XY: 23159 AN XY: 69678

Gnomad4 AFR AF: 0.360

Gnomad4 AMR AF: 0.355

Gnomad4 ASJ AF: 0.303

Gnomad4 EAS AF: 0.0395

Gnomad4 SAS AF: 0.197

Gnomad4 FIN AF: 0.384

Gnomad4 NFE AF: 0.341

Gnomad4 OTH AF: 0.342

Alfa AF: 0.304 Hom.: 9528

Bravo AF: 0.316

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 15, 2018	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	0.60
DANN	Benign	0.38

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs2056387; hg19: chr1-237924112;