rs374709083

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 0P and 3B. BP4_ModerateBP6

The NM_001036.6(RYR3):c.1354C>A(p.Pro452Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000564 in 1,613,400 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00031 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000030 ( 0 hom. )

Consequence

RYR3
NM_001036.6 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:1

Conservation

PhyloP100: 7.77

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: G2P, ClinGen
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: Likely_benign. The variant received -3 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.07917139).

BP6

Variant 15-33580061-C-A is Benign according to our data. Variant chr15-33580061-C-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 461864.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001036.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RYR3	NM_001036.6	MANE Select	c.1354C>A	p.Pro452Thr	missense	Exon 13 of 104	NP_001027.3
	RYR3	NM_001243996.4		c.1354C>A	p.Pro452Thr	missense	Exon 13 of 103	NP_001230925.1	Q15413-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
RYR3	ENST00000634891.2	TSL:1 MANE Select	c.1354C>A	p.Pro452Thr	missense	Exon 13 of 104	ENSP00000489262.1	Q15413-1
RYR3	ENST00000389232.9	TSL:5	c.1354C>A	p.Pro452Thr	missense	Exon 13 of 104	ENSP00000373884.5	A0A0X1KG73
RYR3	ENST00000415757.7	TSL:2	c.1354C>A	p.Pro452Thr	missense	Exon 13 of 103	ENSP00000399610.3	Q15413-2

Frequencies

GnomAD3 genomes

AF:

0.000309

AC:

AN:

152090

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000942

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000393

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:

0.000959

GnomAD2 exomes

AF:

0.0000966

AC:

AN:

248510

AF XY:

0.0000519

show subpopulations

Gnomad AFR exome

AF:

0.00129

Gnomad AMR exome

AF:

0.0000581

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:

0.000331

GnomAD4 exome

AF:

0.0000301

AC:

AN:

1461310

Hom.:

Cov.:

AF XY:

0.0000165

AC XY:

AN XY:

726930

show subpopulations

African (AFR)

AF:

0.000956

AC:

AN:

33480

American (AMR)

AF:

0.000134

AC:

AN:

44708

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39626

South Asian (SAS)

AF:

0.00

AC:

AN:

86208

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53392

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111638

Other (OTH)

AF:

0.0000994

AC:

AN:

60354

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

Exome 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

GnomAD4 genome

AF:

0.000309

AC:

AN:

152090

Hom.:

Cov.:

AF XY:

0.000242

AC XY:

AN XY:

74276

show subpopulations

African (AFR)

AF:

0.000942

AC:

AN:

41408

American (AMR)

AF:

0.000393

AC:

AN:

15256

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5186

South Asian (SAS)

AF:

0.00

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10614

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68022

Other (OTH)

AF:

0.000959

AC:

AN:

2086

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.519

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:

0.000593

Hom.:

Bravo

AF:

0.000382

ESP6500AA

AF:

0.000758

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000107

AC:

ClinVar

ClinVar submissions as Germline

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Epileptic encephalopathy (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.21

BayesDel_noAF

Benign

-0.12

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.81

Eigen

Uncertain

0.45

Eigen_PC

Uncertain

0.52

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.99

M_CAP

Benign

0.034

MetaRNN

Benign

0.079

MetaSVM

Uncertain

0.27

MutationAssessor

Uncertain

2.1

PhyloP100

7.8

PrimateAI

Benign

0.40

PROVEAN

Pathogenic

-4.9

REVEL

Uncertain

0.48

Sift

Benign

0.25

Polyphen

0.80

Vest4

0.36

MVP

0.52

MPC

0.37

ClinPred

0.10

GERP RS

5.2

Varity_R

0.36

gMVP

0.29

Mutation Taster

=31/69

disease causing

(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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over