1-237659974-CTTTT-CTTT

Position:

• chr1-237659974-CTTTT-CTTT

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BS1 BS2

The NM_001035.3(RYR2):​c.8209-4delT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000128 in 1,562,384 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000013 (0 hom.)
• Consequence: RYR2 NM_001035.3 splice_region, intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.909

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]

ACMG classification

Verdict is Benign. Variant got -8 ACMG points.

• BS1: Variant frequency is greater than expected in population amr. gnomad4_exome allele frequency = 0.0000135 (19/1410490) while in subpopulation AMR AF= 0.000169 (6/35556). AF 95% confidence interval is 0.0000734. There are 0 homozygotes in gnomad4_exome. There are 9 alleles in male gnomad4_exome subpopulation. Median coverage is 27. This position pass quality control queck.
• BS2: High AC in GnomAdExome4 at 19 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RYR2	NM_001035.3	c.8209-4delT		splice_region_variant, intron_variant		ENST00000366574.7	NP_001026.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RYR2	ENST00000366574.7	c.8209-10delT		intron_variant		1	NM_001035.3	ENSP00000355533.2
RYR2	ENST00000609119.2	n.8209-10delT		intron_variant		5		ENSP00000499659.2
RYR2	ENST00000660292.2	c.8209-10delT		intron_variant				ENSP00000499787.2
RYR2	ENST00000659194.3	c.8209-10delT		intron_variant				ENSP00000499653.3

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 151894 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000656

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: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000135 AC: 19 AN: 1410490 Hom.: 0 Cov.: 27 AF XY: 0.0000128 AC XY: 9 AN XY: 700862

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000169

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000797

Gnomad4 SAS exome AF: 0.0000131

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000735

Gnomad4 OTH exome AF: 0.0000172

GnomAD4 genome AF: 0.00000658 AC: 1 AN: 151894 Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1 AN XY: 74192

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.0000656

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

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

Publications

LitVar

Other links and lift over

dbSNP: rs876657992; hg19: chr1-237823274;