NM_001035.3:c.6792+50G>A

Variant names:

• chr1-237635042-G-A
• rs41305973
• NM_001035.3:c.6792+50G>A

Variant summary

Our verdict is Benign. The variant received -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:3
• Conservation: PhyloP100: -0.369
• Publications: 3 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=-0.93).
• BP6: Variant 1-237635042-G-A is Benign according to our data. Variant chr1-237635042-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId 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 rank	MANE	Protein	UniProt
RYR2	NM_001035.3	c.6792+50G>A		intron_variant	Intron 44 of 104	ENST00000366574.7	NP_001026.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RYR2	ENST00000366574.7	c.6792+50G>A		intron_variant	Intron 44 of 104	1	NM_001035.3	ENSP00000355533.2
RYR2	ENST00000661330.2	c.6792+50G>A		intron_variant	Intron 44 of 105			ENSP00000499393.2
RYR2	ENST00000609119.2	n.6792+50G>A		intron_variant	Intron 44 of 103	5		ENSP00000499659.2

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

GnomAD2 exomes AF: 0.0798 AC: 8373 AN: 104924 AF XY: 0.0784

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 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

African (AFR) AF: 0.0159 AC: 407 AN: 25538

American (AMR) AF: 0.0470 AC: 933 AN: 19866

Ashkenazi Jewish (ASJ) AF: 0.0396 AC: 783 AN: 19760

East Asian (EAS) AF: 0.000122 AC: 4 AN: 32674

South Asian (SAS) AF: 0.0129 AC: 670 AN: 52000

European-Finnish (FIN) AF: 0.134 AC: 6076 AN: 45376

Middle Eastern (MID) AF: 0.0264 AC: 131 AN: 4954

European-Non Finnish (NFE) AF: 0.121 AC: 109096 AN: 898748

Other (OTH) AF: 0.0873 AC: 4204 AN: 48156

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

African (AFR) AF: 0.0214 AC: 887 AN: 41500

American (AMR) AF: 0.0578 AC: 883 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.0458 AC: 159 AN: 3472

East Asian (EAS) AF: 0.000386 AC: 2 AN: 5178

South Asian (SAS) AF: 0.0110 AC: 53 AN: 4822

European-Finnish (FIN) AF: 0.127 AC: 1343 AN: 10564

Middle Eastern (MID) AF: 0.0340 AC: 10 AN: 294

European-Non Finnish (NFE) AF: 0.117 AC: 7960 AN: 67998

Other (OTH) AF: 0.0679 AC: 143 AN: 2106

Alfa AF: 0.0712 Hom.: 389

Bravo AF: 0.0686

Asia WGS AF: 0.00837 AC: 30 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 26, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

Significance: Likely 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	-0.93
CADD	Benign	0.41
DANN	Benign	0.77
PhyloP100		-0.37
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: rs41305973; hg19: chr1-237798342; COSMIC: COSV107461608;