rs2056387

Variant names:

• chr1-237760812-C-A
• rs2056387
• NM_001035.3:c.11403-143C>A

Your query was ambiguous. Multiple possible variants found:

• chr1-237760812-C-A
• chr1-237760812-C-T

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: Ambry Genetics, Laboratory for Molecular Medicine
• catecholaminergic polymorphic ventricular tachycardia

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, G2P, ClinGen
• catecholaminergic polymorphic ventricular tachycardia 1

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• dilated cardiomyopathy

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen
• 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001035.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RYR2	NM_001035.3	MANE Select	c.11403-143C>A		intron	N/A	NP_001026.2	Q92736-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RYR2	ENST00000366574.7	TSL:1 MANE Select	c.11403-143C>A		intron	N/A	ENSP00000355533.2	Q92736-1
	RYR2	ENST00000661330.2		c.11427-143C>A		intron	N/A	ENSP00000499393.2	A0A590UJF6
	RYR2	ENST00000609119.2	TSL:5	n.*2495-143C>A		intron	N/A	ENSP00000499659.2	A0A590UK06

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

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs2056387;

hg19: chr1-237924112;