NM_001035.3:c.9129-10T>A

Variant names:

• chr1-237700219-T-A
• rs876657993
• NM_001035.3:c.9129-10T>A

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM2 BP4_Strong BP6

The NM_001035.3(RYR2):​c.9129-10T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000003 in 1,331,548 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: not found (cov: 32)
  • Exomes 𝑓: 0.0000030 (0 hom.)
• Consequence: RYR2 NM_001035.3 intron
• Scores: Splicing: ADA: 0.003004
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:2
• Conservation: PhyloP100: 0.553
• 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: ClinGen, G2P, Orphanet
• 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: Likely_benign. The variant received -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 1-237700219-T-A is Benign according to our data. Variant chr1-237700219-T-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 229225.

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.9129-10T>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.9129-10T>A		intron	N/A	ENSP00000355533.2	Q92736-1
	RYR2	ENST00000661330.2		c.9129-10T>A		intron	N/A	ENSP00000499393.2	A0A590UJF6
	RYR2	ENST00000609119.2	TSL:5	n.*164-10T>A		intron	N/A	ENSP00000499659.2	A0A590UK06

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000300 AC: 4 AN: 1331548 Hom.: 0 Cov.: 20 AF XY: 0.00000303 AC XY: 2 AN XY: 659624

African (AFR) AF: 0.00 AC: 0 AN: 30286

American (AMR) AF: 0.00 AC: 0 AN: 35390

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24416

East Asian (EAS) AF: 0.00 AC: 0 AN: 35964

South Asian (SAS) AF: 0.00 AC: 0 AN: 77186

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49700

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5518

European-Non Finnish (NFE) AF: 0.00000393 AC: 4 AN: 1017378

Other (OTH) AF: 0.00 AC: 0 AN: 55710

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	1	not specified (2)
-	1	-	Catecholaminergic polymorphic ventricular tachycardia (1)
-	-	1	Catecholaminergic polymorphic ventricular tachycardia 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	6.5
DANN	Benign	0.78
PhyloP100		0.55

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0030
dbscSNV1_RF	Benign	0.20
SpliceAI score (max)		0.060		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: rs876657993; hg19: chr1-237863519;