Genetic Variant RYR3:c.172-122A>G (chr15-33503509-A-G) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_001036.6(RYR3):c.172-122A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.986 in 622,018 control chromosomes in the GnomAD database, including 302,715 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.97 ( 71886 hom., cov: 32)

Exomes 𝑓: 0.99 ( 230829 hom. )

Consequence

RYR3
NM_001036.6 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.0130

Publications

4 publications found

Variant links:

Genes affected

RYR3 (HGNC:10485): (ryanodine receptor 3) The protein encoded by this gene is a ryanodine receptor, which functions to release calcium from intracellular storage for use in many cellular processes. For example, the encoded protein is involved in skeletal muscle contraction by releasing calcium from the sarcoplasmic reticulum followed by depolarization of T-tubules. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Sep 2011]

RYR3 Gene-Disease associations (from GenCC):

genetic developmental and epileptic encephalopathy
Inheritance: AD Classification: LIMITED Submitted by: ClinGen, G2P
congenital myopathy
Inheritance: AR Classification: NO_KNOWN Submitted by: ClinGen

RYR3 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.82).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.985 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RYR3	NM_001036.6 link	c.172-122A>G		intron_variant	Intron 2 of 103	ENST00000634891.2	NP_001027.3	Q15413-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RYR3	ENST00000634891.2 link	c.172-122A>G		intron_variant	Intron 2 of 103	1	NM_001036.6	ENSP00000489262.1		Q15413-1

Frequencies

GnomAD3 genomes

AF:

0.971

AC:

147742

AN:

152182

Hom.:

71828

Cov.:

show subpopulations

Gnomad AFR

AF:

0.912

Gnomad AMI

AF:

0.973

Gnomad AMR

AF:

0.991

Gnomad ASJ

AF:

0.999

Gnomad EAS

AF:

1.00

Gnomad SAS

AF:

0.998

Gnomad FIN

AF:

0.999

Gnomad MID

AF:

0.991

Gnomad NFE

AF:

0.992

Gnomad OTH

AF:

0.979

GnomAD4 exome

AF:

0.991

AC:

465602

AN:

469718

Hom.:

230829

AF XY:

0.992

AC XY:

244708

AN XY:

246702

show subpopulations

African (AFR)

AF:

0.910

AC:

11654

AN:

12810

American (AMR)

AF:

0.992

AC:

19081

AN:

19236

Ashkenazi Jewish (ASJ)

AF:

0.999

AC:

13974

AN:

13994

East Asian (EAS)

AF:

1.00

AC:

30451

AN:

30452

South Asian (SAS)

AF:

0.997

AC:

42361

AN:

42488

European-Finnish (FIN)

AF:

0.999

AC:

39873

AN:

39928

Middle Eastern (MID)

AF:

0.990

AC:

3536

AN:

3572

European-Non Finnish (NFE)

AF:

0.992

AC:

278855

AN:

281104

Other (OTH)

AF:

0.988

AC:

25817

AN:

26134

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.510

Heterozygous variant carriers

185

370

555

740

925

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1354

2708

4062

5416

6770

<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

AF:

0.971

AC:

147860

AN:

152300

Hom.:

71886

Cov.:

AF XY:

0.972

AC XY:

72383

AN XY:

74478

show subpopulations

African (AFR)

AF:

0.913

AC:

37912

AN:

41546

American (AMR)

AF:

0.991

AC:

15160

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.999

AC:

3468

AN:

3472

East Asian (EAS)

AF:

1.00

AC:

5179

AN:

5180

South Asian (SAS)

AF:

0.998

AC:

4812

AN:

4820

European-Finnish (FIN)

AF:

0.999

AC:

10615

AN:

10622

Middle Eastern (MID)

AF:

0.993

AC:

292

AN:

294

European-Non Finnish (NFE)

AF:

0.992

AC:

67467

AN:

68038

Other (OTH)

AF:

0.979

AC:

2068

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

214

428

642

856

1070

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

914

1828

2742

3656

4570

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.984

Hom.:

32641

Bravo

AF:

0.967

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.82

CADD

Benign

1.9

(source)

DANN

Benign

0.70

PhyloP100

-0.013

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over