NM_001036.6:c.5834C>T

Variant names:

Variant summary

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

The NM_001036.6(RYR3):c.5834C>T(p.Pro1945Leu) variant causes a missense change. The variant allele was found at a frequency of 0.0000282 in 1,594,622 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000024 ( 0 hom. )

Consequence

RYR3
NM_001036.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 4.20

Publications

1 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:

ENSG00000295407 (HGNC:):

ENSG00000295407 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RYR3	NM_001036.6 link	c.5834C>T	p.Pro1945Leu	missense_variant	Exon 38 of 104	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.5834C>T	p.Pro1945Leu	missense_variant	Exon 38 of 104	1	NM_001036.6	ENSP00000489262.1		Q15413-1

Frequencies

GnomAD3 genomes

AF:

0.0000658

AC:

AN:

152004

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000217

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00318

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000217

AC:

AN:

230266

AF XY:

0.0000240

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000468

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000243

AC:

AN:

1442500

Hom.:

Cov.:

AF XY:

0.0000307

AC XY:

AN XY:

716942

show subpopulations

African (AFR)

AF:

0.0000621

AC:

AN:

32230

American (AMR)

AF:

0.00

AC:

AN:

39732

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24754

East Asian (EAS)

AF:

0.0000506

AC:

AN:

39560

South Asian (SAS)

AF:

0.0000242

AC:

AN:

82694

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52940

Middle Eastern (MID)

AF:

0.00124

AC:

AN:

5636

European-Non Finnish (NFE)

AF:

0.0000190

AC:

AN:

1105466

Other (OTH)

AF:

0.0000168

AC:

AN:

59488

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.459

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000657

AC:

AN:

152122

Hom.:

Cov.:

AF XY:

0.0000941

AC XY:

AN XY:

74370

show subpopulations

African (AFR)

AF:

0.000217

AC:

AN:

41502

American (AMR)

AF:

0.00

AC:

AN:

15274

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5172

South Asian (SAS)

AF:

0.00

AC:

AN:

4796

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10580

Middle Eastern (MID)

AF:

0.00342

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68010

Other (OTH)

AF:

0.00

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.520

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0000658

Hom.:

Bravo

AF:

0.0000529

ESP6500AA

AF:

0.000255

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jun 21, 2021

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.5834C>T (p.P1945L) alteration is located in exon 38 (coding exon 38) of the RYR3 gene. This alteration results from a C to T substitution at nucleotide position 5834, causing the proline (P) at amino acid position 1945 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Epileptic encephalopathy

Uncertain:1

Aug 31, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces proline with leucine at codon 1945 of the RYR3 protein (p.Pro1945Leu). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and leucine. This variant is present in population databases (rs375210672, ExAC 0.003%). This variant has not been reported in the literature in individuals affected with RYR3-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.079

BayesDel_addAF

Uncertain

0.038

BayesDel_noAF

Uncertain

-0.050

CADD

Benign

(source)

DANN

Benign

0.85

DEOGEN2

Uncertain

0.69

D;.;.;.;.

Eigen

Benign

-0.39

Eigen_PC

Benign

-0.25

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.91

D;D;D;D;D

M_CAP

Benign

0.067

MetaRNN

Uncertain

0.54

D;D;D;D;D

MetaSVM

Uncertain

0.20

MutationAssessor

Benign

1.8

L;L;.;.;.

PhyloP100

4.2

PrimateAI

Benign

0.46

PROVEAN

Pathogenic

-4.7

.;D;D;.;.

REVEL

Uncertain

0.34

Sift

Benign

0.18

.;T;T;.;.

Polyphen

0.051

B;B;.;.;.

Vest4

0.67

MVP

0.41

MPC

0.20

ClinPred

0.56

GERP RS

4.5

Varity_R

0.22

gMVP

0.38

Mutation Taster

=65/35

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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NM_001036.6:c.5834C>T

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