dbSNP rs186614396: RYR3:p.Ala2901Ala (chr15-33757594-C-T) – ACMG Classification: Benign (-10 pts)

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4BP6_Very_StrongBP7

The NM_001036.6(RYR3):c.8703C>T(p.Ala2901Ala) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000956 in 1,609,528 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.00070 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00098 ( 0 hom. )

Consequence

RYR3
NM_001036.6 splice_region, synonymous

Scores

Splicing: ADA: 0.1576

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 2.49

Publications

0 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 -10 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.18).

BP6

Variant 15-33757594-C-T is Benign according to our data. Variant chr15-33757594-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 461973.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=2.49 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RYR3	NM_001036.6 link	c.8703C>T	p.Ala2901Ala	splice_region_variant, synonymous_variant	Exon 60 of 104	ENST00000634891.2	NP_001027.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RYR3	ENST00000634891.2 link	c.8703C>T	p.Ala2901Ala	splice_region_variant, synonymous_variant	Exon 60 of 104	1	NM_001036.6	ENSP00000489262.1

Frequencies

GnomAD3 genomes

AF:

0.000698

AC:

106

AN:

151940

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000242

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000386

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000284

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00131

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000589

AC:

142

AN:

241158

AF XY:

0.000529

show subpopulations

Gnomad AFR exome

AF:

0.000137

Gnomad AMR exome

AF:

0.000296

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000400

Gnomad FIN exome

AF:

0.000236

Gnomad NFE exome

AF:

0.00103

Gnomad OTH exome

AF:

0.000845

GnomAD4 exome

AF:

0.000983

AC:

1432

AN:

1457470

Hom.:

Cov.:

AF XY:

0.000937

AC XY:

679

AN XY:

724386

show subpopulations

African (AFR)

AF:

0.0000599

AC:

AN:

33404

American (AMR)

AF:

0.000294

AC:

AN:

44252

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26002

East Asian (EAS)

AF:

0.000152

AC:

AN:

39546

South Asian (SAS)

AF:

0.0000118

AC:

AN:

84810

European-Finnish (FIN)

AF:

0.000394

AC:

AN:

53244

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.00121

AC:

1342

AN:

1110210

Other (OTH)

AF:

0.000780

AC:

AN:

60238

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.459

Heterozygous variant carriers

138

208

277

346

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

104

156

208

260

<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:

0.000697

AC:

106

AN:

152058

Hom.:

Cov.:

AF XY:

0.000673

AC XY:

AN XY:

74326

show subpopulations

African (AFR)

AF:

0.000241

AC:

AN:

41462

American (AMR)

AF:

0.000131

AC:

AN:

15276

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.000387

AC:

AN:

5168

South Asian (SAS)

AF:

0.00

AC:

AN:

4810

European-Finnish (FIN)

AF:

0.000284

AC:

AN:

10566

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00131

AC:

AN:

67992

Other (OTH)

AF:

0.00

AC:

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

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

Alfa

AF:

0.000777

Hom.:

Bravo

AF:

0.000661

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Epileptic encephalopathy

Benign:1

Oct 11, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:1

Feb 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

RYR3: BP4 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.18

CADD

Benign

(source)

DANN

Benign

0.79

PhyloP100

2.5

Mutation Taster

=73/27

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.16

dbscSNV1_RF

Benign

0.32

SpliceAI score (max)

0.12

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

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over