Genetic Variant NM_001035.3:c.3599-12_3599-9dupTTTT (chr1-237589774-A-ATTTT) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.

The NM_001035.3(RYR2):c.3599-12_3599-9dupTTTT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 0)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

RYR2
NM_001035.3 splice_region, intron

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.467

Publications

0 publications found

Variant links:

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

RYR2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RYR2	NM_001035.3 link	c.3599-12_3599-9dupTTTT		splice_region_variant, intron_variant	Intron 29 of 104	ENST00000366574.7	NP_001026.2	Q92736-1

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
RYR2	ENST00000366574.7 link	c.3599-19_3599-18insTTTT	intron_variant	Intron 29 of 104	1	NM_001035.3	ENSP00000355533.2	Q92736-1
RYR2	ENST00000661330.2 link	c.3599-19_3599-18insTTTT	intron_variant	Intron 29 of 105			ENSP00000499393.2	A0A590UJF6
RYR2	ENST00000609119.2 link	n.3599-19_3599-18insTTTT	intron_variant	Intron 29 of 103	5		ENSP00000499659.2	A0A590UK06

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.0000271

AC:

AN:

221074

AF XY:

0.0000168

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000992

Gnomad NFE exome

AF:

0.0000298

Gnomad OTH exome

AF:

0.000183

GnomAD4 exome

AF:

0.00000140

AC:

AN:

1428172

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

710734

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

32300

American (AMR)

AF:

0.0000230

AC:

AN:

43500

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25546

East Asian (EAS)

AF:

0.00

AC:

AN:

38960

South Asian (SAS)

AF:

0.00

AC:

AN:

83762

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52648

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5696

European-Non Finnish (NFE)

AF:

9.20e-7

AC:

AN:

1086706

Other (OTH)

AF:

0.00

AC:

AN:

59054

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.250

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

0.47

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over