Genetic Variant RYR2:c.464-8A>G (chr1-237377315-A-G) – ACMG Classification: Likely_benign (-6 pts)

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 2P and 8B. PM2BP4_StrongBS1

The NM_001035.3(RYR2):c.464-8A>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000208 in 1,444,786 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 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: not found (cov: 32)

Exomes 𝑓: 0.0000021 ( 1 hom. )

Consequence

RYR2
NM_001035.3 splice_region, intron

Scores

Splicing: ADA: 0.00006701

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -2.49

Publications

14 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:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -6 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.83).

BS1

Variant frequency is greater than expected in population amr. GnomAdExome4 allele frequency = 0.00000208 (3/1444786) while in subpopulation AMR AF = 0.0000704 (3/42598). AF 95% confidence interval is 0.0000187. There are 1 homozygotes in GnomAdExome4. There are 3 alleles in the male GnomAdExome4 subpopulation. Median coverage is 28. This position passed quality control check.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RYR2	NM_001035.3 link	c.464-8A>G		splice_region_variant, intron_variant	Intron 7 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.464-8A>G	splice_region_variant, intron_variant	Intron 7 of 104	1	NM_001035.3	ENSP00000355533.2	Q92736-1
RYR2	ENST00000661330.2 link	c.464-8A>G	splice_region_variant, intron_variant	Intron 7 of 105			ENSP00000499393.2	A0A590UJF6
RYR2	ENST00000609119.2 link	n.464-8A>G	splice_region_variant, intron_variant	Intron 7 of 103	5		ENSP00000499659.2	A0A590UK06

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.0000125

AC:

AN:

239434

AF XY:

0.0000231

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000938

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000208

AC:

AN:

1444786

Hom.:

Cov.:

AF XY:

0.00000418

AC XY:

AN XY:

717814

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32870

American (AMR)

AF:

0.0000704

AC:

AN:

42598

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25560

East Asian (EAS)

AF:

0.00

AC:

AN:

39410

South Asian (SAS)

AF:

0.00

AC:

AN:

83526

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53092

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5652

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1102416

Other (OTH)

AF:

0.00

AC:

AN:

59662

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.575

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

17859

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.83

CADD

Benign

0.15

(source)

DANN

Benign

0.53

PhyloP100

-2.5

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000067

dbscSNV1_RF

Benign

0.0080

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over