rs6683048

chr1-237625486-G-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_001035.3(RYR2):c.6023-175G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.168 in 152,068 control chromosomes in the GnomAD database, including 2,581 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.17 (2581 hom., cov: 31)
• Consequence: RYR2 NM_001035.3 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.971

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 1-237625486-G-A is Benign according to our data. Variant chr1-237625486-G-A is described in ClinVar as [Benign]. Clinvar id is 672076.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.289 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RYR2	NM_001035.3	c.6023-175G>A		intron_variant		ENST00000366574.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RYR2	ENST00000366574.7	c.6023-175G>A		intron_variant		1	NM_001035.3	P1
RYR2	ENST00000659194.3	c.6023-175G>A		intron_variant
RYR2	ENST00000660292.2	c.6023-175G>A		intron_variant
RYR2	ENST00000609119.2	c.6023-175G>A		intron_variant, NMD_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.168 AC: 25498 AN: 151950 Hom.: 2580 Cov.: 31

Gnomad AFR AF: 0.294

Gnomad AMI AF: 0.182

Gnomad AMR AF: 0.132

Gnomad ASJ AF: 0.0671

Gnomad EAS AF: 0.141

Gnomad SAS AF: 0.0754

Gnomad FIN AF: 0.161

Gnomad MID AF: 0.0728

Gnomad NFE AF: 0.116

Gnomad OTH AF: 0.131

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.168 AC: 25526 AN: 152068 Hom.: 2581 Cov.: 31 AF XY: 0.165 AC XY: 12291 AN XY: 74328

Gnomad4 AFR AF: 0.293

Gnomad4 AMR AF: 0.132

Gnomad4 ASJ AF: 0.0671

Gnomad4 EAS AF: 0.140

Gnomad4 SAS AF: 0.0750

Gnomad4 FIN AF: 0.161

Gnomad4 NFE AF: 0.116

Gnomad4 OTH AF: 0.132

Alfa AF: 0.120 Hom.: 1737

Bravo AF: 0.172

Asia WGS AF: 0.124 AC: 432 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 19, 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	-0.86
Cadd	Benign	12
Dann	Benign	0.54

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.22		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.22		Position offset: 31

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs6683048; hg19: chr1-237788786;