chr1-237659956-A-C

Variant names:

• chr1-237659956-A-C
• rs10925485
• NM_001035.3:c.8209-29A>C

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.8209-29A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0504 in 1,484,206 control chromosomes in the GnomAD database, including 2,139 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). There are indicators that this mutation may affect the branch point..

• Frequency:
  • Genomes: 𝑓 0.060 (331 hom., cov: 32)
  • Exomes 𝑓: 0.049 (1808 hom.)
• Consequence: RYR2 NM_001035.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.925

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: This position, referring to a specific DNA site, is a probable branch point but is likely benign (scored 3 / 10, using the threshold of <=3). The score ranges from 0 to 10, with values ≤3 considered benign and >5 classified as pathogenic. Computational evidence support a benign effect (BayesDel_noAF=-0.69).
• BP6: Variant 1-237659956-A-C is Benign according to our data. Variant chr1-237659956-A-C is described in ClinVar as [Benign]. Clinvar id is 257218.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0883 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RYR2	NM_001035.3	c.8209-29A>C		intron_variant	Intron 54 of 104	ENST00000366574.7	NP_001026.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RYR2	ENST00000366574.7	c.8209-29A>C		intron_variant	Intron 54 of 104	1	NM_001035.3	ENSP00000355533.2
RYR2	ENST00000609119.2	n.8209-29A>C		intron_variant	Intron 54 of 103	5		ENSP00000499659.2
RYR2	ENST00000660292.2	c.8209-29A>C		intron_variant	Intron 54 of 105			ENSP00000499787.2
RYR2	ENST00000659194.3	c.8209-29A>C		intron_variant	Intron 54 of 104			ENSP00000499653.3

Frequencies

GnomAD3 genomes AF: 0.0597 AC: 9082 AN: 152128 Hom.: 329 Cov.: 32

Gnomad AFR AF: 0.0907

Gnomad AMI AF: 0.0252

Gnomad AMR AF: 0.0482

Gnomad ASJ AF: 0.0767

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00703

Gnomad FIN AF: 0.0535

Gnomad MID AF: 0.0633

Gnomad NFE AF: 0.0522

Gnomad OTH AF: 0.0598

GnomAD3 exomes AF: 0.0452 AC: 8864 AN: 196322 Hom.: 246 AF XY: 0.0444 AC XY: 4754 AN XY: 107012

Gnomad AFR exome AF: 0.0884

Gnomad AMR exome AF: 0.0308

Gnomad ASJ exome AF: 0.0739

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00665

Gnomad FIN exome AF: 0.0582

Gnomad NFE exome AF: 0.0535

Gnomad OTH exome AF: 0.0466

GnomAD4 exome AF: 0.0493 AC: 65686 AN: 1331962 Hom.: 1808 Cov.: 19 AF XY: 0.0481 AC XY: 32016 AN XY: 665620

Gnomad4 AFR exome AF: 0.0971

Gnomad4 AMR exome AF: 0.0330

Gnomad4 ASJ exome AF: 0.0715

Gnomad4 EAS exome AF: 0.0000268

Gnomad4 SAS exome AF: 0.00684

Gnomad4 FIN exome AF: 0.0573

Gnomad4 NFE exome AF: 0.0526

Gnomad4 OTH exome AF: 0.0488

GnomAD4 genome AF: 0.0597 AC: 9096 AN: 152244 Hom.: 331 Cov.: 32 AF XY: 0.0584 AC XY: 4348 AN XY: 74444

Gnomad4 AFR AF: 0.0907

Gnomad4 AMR AF: 0.0481

Gnomad4 ASJ AF: 0.0767

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00704

Gnomad4 FIN AF: 0.0535

Gnomad4 NFE AF: 0.0522

Gnomad4 OTH AF: 0.0591

Alfa AF: 0.0559 Hom.: 67

Bravo AF: 0.0605

Asia WGS AF: 0.00983 AC: 34 AN: 3474

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 18, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.69
CADD	Benign	7.5
DANN	Benign	0.72
BranchPoint Hunter		3.0

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: rs10925485; hg19: chr1-237823256;