rs562147027

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2BP4_StrongBP6

The NM_001036.6(RYR3):c.17A>G(p.Glu6Gly) variant causes a missense change. The variant allele was found at a frequency of 0.000191 in 1,582,534 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 0.00027 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00018 ( 0 hom. )

Consequence

RYR3
NM_001036.6 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 6.92

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.009333372).

BP6

Variant 15-33311062-A-G is Benign according to our data. Variant chr15-33311062-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 531143.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RYR3	NM_001036.6 linkuse as main transcript	c.17A>G	p.Glu6Gly	missense_variant	1/104	ENST00000634891.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RYR3	ENST00000634891.2 linkuse as main transcript	c.17A>G	p.Glu6Gly	missense_variant	1/104	1	NM_001036.6	P4	Q15413-1

Frequencies

GnomAD3 genomes

AF:

0.000270

AC:

AN:

151940

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00836

Gnomad EAS

AF:

0.00156

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000588

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000454

AC:

100

AN:

220478

Hom.:

AF XY:

0.000504

AC XY:

AN XY:

121102

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000327

Gnomad ASJ exome

AF:

0.00845

Gnomad EAS exome

AF:

0.000708

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000888

Gnomad OTH exome

AF:

0.000390

GnomAD4 exome

AF:

0.000183

AC:

262

AN:

1430476

Hom.:

Cov.:

AF XY:

0.000184

AC XY:

131

AN XY:

711212

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000242

Gnomad4 ASJ exome

AF:

0.00757

Gnomad4 EAS exome

AF:

0.000555

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000255

Gnomad4 OTH exome

AF:

0.000356

GnomAD4 genome

AF:

0.000270

AC:

AN:

152058

Hom.:

Cov.:

AF XY:

0.000229

AC XY:

AN XY:

74330

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00836

Gnomad4 EAS

AF:

0.00156

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000588

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.00104

Hom.:

Bravo

AF:

0.000238

ExAC

AF:

0.000381

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 14, 2022

The c.17A>G (p.E6G) alteration is located in exon 1 (coding exon 1) of the RYR3 gene. This alteration results from a A to G substitution at nucleotide position 17, causing the glutamic acid (E) at amino acid position 6 to be replaced by a glycine (G). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Epileptic encephalopathy

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Nov 17, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.10

BayesDel_noAF

Uncertain

-0.010

Cadd

Uncertain

Dann

Uncertain

1.0

DEOGEN2

Benign

0.23

T;.;.;.;.

Eigen

Benign

0.011

Eigen_PC

Benign

0.17

FATHMM_MKL

Uncertain

0.89

LIST_S2

Benign

0.74

T;T;T;T;T

M_CAP

Pathogenic

0.52

MetaRNN

Benign

0.0093

T;T;T;T;T

MetaSVM

Uncertain

0.66

MutationAssessor

Benign

1.0

L;L;.;.;.

MutationTaster

Benign

0.79

D;D

PrimateAI

Uncertain

0.61

Polyphen

0.32

B;B;.;.;.

Vest4

0.49

MVP

0.47

MPC

0.21

ClinPred

0.099

GERP RS

5.2

Varity_R

0.20

gMVP

0.29

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over