chr1-237761038-A-C

Variant names:

• chr1-237761038-A-C
• rs794728702
• NM_001035.3:c.11476+10A>C

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_001035.3(RYR2):​c.11476+10A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000278 in 1,512,728 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000027 (0 hom.)
• Consequence: RYR2 NM_001035.3 intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: 0.00
• Publications: 0 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant 1-237761038-A-C is Benign according to our data. Variant chr1-237761038-A-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 201181.
• BS1: Variant frequency is greater than expected in population nfe. GnomAdExome4 allele frequency = 0.0000272 (37/1360562) while in subpopulation NFE AF = 0.0000356 (37/1037986). AF 95% confidence interval is 0.0000263. There are 0 homozygotes in GnomAdExome4. There are 12 alleles in the male GnomAdExome4 subpopulation. Median coverage is 23. This position passed quality control check.
• BS2: High AC in GnomAd4 at 5 AD gene.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RYR2	NM_001035.3	MANE Select	c.11476+10A>C		intron	N/A	NP_001026.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RYR2	ENST00000366574.7	TSL:1 MANE Select	c.11476+10A>C		intron	N/A	ENSP00000355533.2
	RYR2	ENST00000661330.2		c.11500+10A>C		intron	N/A	ENSP00000499393.2
	RYR2	ENST00000609119.2	TSL:5	n.*2568+10A>C		intron	N/A	ENSP00000499659.2

Frequencies

GnomAD3 genomes AF: 0.0000329 AC: 5 AN: 152166 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000272 AC: 37 AN: 1360562 Hom.: 0 Cov.: 23 AF XY: 0.0000178 AC XY: 12 AN XY: 675484

African (AFR) AF: 0.00 AC: 0 AN: 31226

American (AMR) AF: 0.00 AC: 0 AN: 37760

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24948

East Asian (EAS) AF: 0.00 AC: 0 AN: 36822

South Asian (SAS) AF: 0.00 AC: 0 AN: 78756

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50446

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5626

European-Non Finnish (NFE) AF: 0.0000356 AC: 37 AN: 1037986

Other (OTH) AF: 0.00 AC: 0 AN: 56992

GnomAD4 genome AF: 0.0000329 AC: 5 AN: 152166 Hom.: 0 Cov.: 32 AF XY: 0.0000404 AC XY: 3 AN XY: 74346

African (AFR) AF: 0.0000483 AC: 2 AN: 41438

American (AMR) AF: 0.00 AC: 0 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5196

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68030

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.000107 Hom.: 0

Bravo AF: 0.0000378

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	-	Cardiomyopathy (1)
-	-	1	Catecholaminergic polymorphic ventricular tachycardia 1 (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	2.9
DANN	Benign	0.61
PhyloP100		0.0

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

Other links and lift over

dbSNP: rs794728702; hg19: chr1-237924338;