Genetic Variant RYR3:p.Arg2705Leu (chr15-33748238-G-T) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001036.6(RYR3):c.8114G>T(p.Arg2705Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,542 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R2705Q) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

RYR3
NM_001036.6 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 7.71

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:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RYR3	NM_001036.6 link	c.8114G>T	p.Arg2705Leu	missense_variant	Exon 54 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.8114G>T	p.Arg2705Leu	missense_variant	Exon 54 of 104	1	NM_001036.6	ENSP00000489262.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461542

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727056

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33470

American (AMR)

AF:

0.00

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26130

East Asian (EAS)

AF:

0.00

AC:

AN:

39686

South Asian (SAS)

AF:

0.00

AC:

AN:

86240

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53390

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5720

European-Non Finnish (NFE)

AF:

8.99e-7

AC:

AN:

1111826

Other (OTH)

AF:

0.00

AC:

AN:

60358

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

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.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.23

BayesDel_addAF

Pathogenic

0.32

BayesDel_noAF

Pathogenic

0.22

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.66

D;.;.;.;.

Eigen

Uncertain

0.20

Eigen_PC

Uncertain

0.35

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.96

D;D;D;D;D

M_CAP

Benign

0.068

MetaRNN

Uncertain

0.72

D;D;D;D;D

MetaSVM

Uncertain

0.66

MutationAssessor

Benign

1.7

L;L;.;.;.

PhyloP100

7.7

PrimateAI

Uncertain

0.54

PROVEAN

Pathogenic

-5.3

.;D;.;.;.

REVEL

Uncertain

0.64

Sift

Uncertain

0.023

.;D;.;.;.

Polyphen

0.0090

B;B;.;.;.

Vest4

0.78

MutPred

0.38

Loss of MoRF binding (P = 0.0162);Loss of MoRF binding (P = 0.0162);.;Loss of MoRF binding (P = 0.0162);.;

MVP

0.79

MPC

0.27

ClinPred

0.99

GERP RS

5.2

Varity_R

0.75

gMVP

0.57

Mutation Taster

=59/41

polymorphism

(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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over