NM_001035.3:c.11403-143C>A

Variant names:

• chr1-237760812-C-A
• rs2056387
• NM_001035.3:c.11403-143C>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.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
• Publications: 7 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=-0.78).
• BP6: Variant 1-237760812-C-A is Benign according to our data. Variant chr1-237760812-C-A is described in ClinVar as Benign. ClinVar VariationId 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 rank	MANE	Protein	UniProt
RYR2	NM_001035.3	c.11403-143C>A		intron_variant	Intron 83 of 104	ENST00000366574.7	NP_001026.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RYR2	ENST00000366574.7	c.11403-143C>A		intron_variant	Intron 83 of 104	1	NM_001035.3	ENSP00000355533.2
RYR2	ENST00000661330.2	c.11427-143C>A		intron_variant	Intron 84 of 105			ENSP00000499393.2
RYR2	ENST00000609119.2	n.*2495-143C>A		intron_variant	Intron 82 of 103	5		ENSP00000499659.2

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

African (AFR) AF: 0.349 AC: 3589 AN: 10292

American (AMR) AF: 0.342 AC: 5182 AN: 15172

Ashkenazi Jewish (ASJ) AF: 0.283 AC: 4033 AN: 14242

East Asian (EAS) AF: 0.0431 AC: 1204 AN: 27934

South Asian (SAS) AF: 0.192 AC: 8170 AN: 42600

European-Finnish (FIN) AF: 0.372 AC: 12748 AN: 34294

Middle Eastern (MID) AF: 0.289 AC: 540 AN: 1868

European-Non Finnish (NFE) AF: 0.336 AC: 82538 AN: 245438

Other (OTH) AF: 0.309 AC: 7233 AN: 23406

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

African (AFR) AF: 0.360 AC: 13993 AN: 38888

American (AMR) AF: 0.355 AC: 5060 AN: 14268

Ashkenazi Jewish (ASJ) AF: 0.303 AC: 1001 AN: 3302

East Asian (EAS) AF: 0.0395 AC: 194 AN: 4912

South Asian (SAS) AF: 0.197 AC: 923 AN: 4674

European-Finnish (FIN) AF: 0.384 AC: 3882 AN: 10102

Middle Eastern (MID) AF: 0.362 AC: 100 AN: 276

European-Non Finnish (NFE) AF: 0.341 AC: 21456 AN: 62932

Other (OTH) AF: 0.342 AC: 675 AN: 1972

Alfa AF: 0.310 Hom.: 13341

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

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 15, 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	0.60
DANN	Benign	0.38
PhyloP100		-0.41
Mutation Taster		=30/70	disease causing

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

Other links and lift over

dbSNP: rs2056387; hg19: chr1-237924112;