chr15-33748227-T-G

Position:

chr15-33748227-T-G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001036.6(RYR3):c.8103T>G(p.Asn2701Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000434 in 1,613,514 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.00029 ( 1 hom., cov: 32)

Exomes 𝑓: 0.000018 ( 0 hom. )

Consequence

RYR3
NM_001036.6 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.173

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:

RYR3 (HGNC:):

RYR3 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.030047715).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RYR3	NM_001036.6 linkuse as main transcript	c.8103T>G	p.Asn2701Lys	missense_variant	54/104	ENST00000634891.2	NP_001027.3	Q15413-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RYR3	ENST00000634891.2 linkuse as main transcript	c.8103T>G	p.Asn2701Lys	missense_variant	54/104	1	NM_001036.6	ENSP00000489262.1		Q15413-1

Frequencies

GnomAD3 genomes

AF:

0.000290

AC:

AN:

151780

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000484

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00138

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:

0.0000147

Gnomad OTH

AF:

0.000960

GnomAD3 exomes

AF:

0.0000562

AC:

AN:

248938

Hom.:

AF XY:

0.0000518

AC XY:

AN XY:

135062

show subpopulations

Gnomad AFR exome

AF:

0.000452

Gnomad AMR exome

AF:

0.000116

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000497

GnomAD4 exome

AF:

0.0000178

AC:

AN:

1461616

Hom.:

Cov.:

AF XY:

0.0000165

AC XY:

AN XY:

727084

show subpopulations

Gnomad4 AFR exome

AF:

0.000329

Gnomad4 AMR exome

AF:

0.000201

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.0000994

GnomAD4 genome

AF:

0.000290

AC:

AN:

151898

Hom.:

Cov.:

AF XY:

0.000256

AC XY:

AN XY:

74232

show subpopulations

Gnomad4 AFR

AF:

0.000483

Gnomad4 AMR

AF:

0.00138

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.000950

Alfa

AF:

0.0000155

Hom.:

Bravo

AF:

0.000336

ESP6500AA

AF:

0.00102

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000662

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 22, 2021

The c.8103T>G (p.N2701K) alteration is located in exon 54 (coding exon 54) of the RYR3 gene. This alteration results from a T to G substitution at nucleotide position 8103, causing the asparagine (N) at amino acid position 2701 to be replaced by a lysine (K). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Epileptic encephalopathy

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jul 06, 2022

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. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 461963). This variant has not been reported in the literature in individuals affected with RYR3-related conditions. This variant is present in population databases (rs192820783, gnomAD 0.05%). This sequence change replaces asparagine, which is neutral and polar, with lysine, which is basic and polar, at codon 2701 of the RYR3 protein (p.Asn2701Lys). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.18

BayesDel_addAF

Benign

-0.23

BayesDel_noAF

Benign

-0.23

CADD

Benign

DANN

Benign

0.90

DEOGEN2

Benign

0.25

T;.;.;.;.

Eigen

Benign

-0.58

Eigen_PC

Benign

-0.39

FATHMM_MKL

Uncertain

0.91

LIST_S2

Uncertain

0.96

D;D;D;D;D

M_CAP

Benign

0.039

MetaRNN

Benign

0.030

T;T;T;T;T

MetaSVM

Benign

-0.35

MutationAssessor

Benign

-0.27

N;N;.;.;.

PrimateAI

Uncertain

0.65

PROVEAN

Benign

-1.3

.;N;.;.;.

REVEL

Benign

0.23

Sift

Benign

0.71

.;T;.;.;.

Polyphen

0.054

B;B;.;.;.

Vest4

0.36

MutPred

0.34

Gain of ubiquitination at N2701 (P = 0.0014);Gain of ubiquitination at N2701 (P = 0.0014);.;Gain of ubiquitination at N2701 (P = 0.0014);.;

MVP

0.77

MPC

0.22

ClinPred

0.021

GERP RS

2.9

Varity_R

0.20

gMVP

0.19

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