19-38473699-C-T

Position:

chr19-38473699-C-T

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 1P and 5B. PP2BP4_StrongBP6

The NM_000540.3(RYR1):c.4088C>T(p.Ala1363Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000155 in 1,545,066 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00075 ( 1 hom., cov: 31)

Exomes 𝑓: 0.000090 ( 1 hom. )

Consequence

RYR1
NM_000540.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:4

Conservation

PhyloP100: 0.868

Variant links:

Genes affected

RYR1 (HGNC:10483): (ryanodine receptor 1) This gene encodes a ryanodine receptor found in skeletal muscle. The encoded protein functions as a calcium release channel in the sarcoplasmic reticulum but also serves to connect the sarcoplasmic reticulum and transverse tubule. Mutations in this gene are associated with malignant hyperthermia susceptibility, central core disease, and minicore myopathy with external ophthalmoplegia. Alternatively spliced transcripts encoding different isoforms have been described. [provided by RefSeq, Jul 2008]

RYR1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -4 ACMG points.

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), RYR1. . Gene score misZ 1.918 (greater than the threshold 3.09). Trascript score misZ 3.9788 (greater than threshold 3.09). GenCC has associacion of gene with King-Denborough syndrome, congenital multicore myopathy with external ophthalmoplegia, autosomal recessive centronuclear myopathy, RYR1-related myopathy, lethal multiple pterygium syndrome, malignant hyperthermia of anesthesia, benign Samaritan congenital myopathy, malignant hyperthermia, susceptibility to, 1, congenital myopathy with myasthenic-like onset, central core myopathy.

BP4

Computational evidence support a benign effect (MetaRNN=0.020543128).

BP6

Variant 19-38473699-C-T is Benign according to our data. Variant chr19-38473699-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 201150.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=1, Benign=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RYR1	NM_000540.3 linkuse as main transcript	c.4088C>T	p.Ala1363Val	missense_variant	28/106	ENST00000359596.8	NP_000531.2	P21817-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
RYR1	ENST00000359596.8 linkuse as main transcript	c.4088C>T	p.Ala1363Val	missense_variant	28/106	5	NM_000540.3	ENSP00000352608.2	P21817-1
RYR1	ENST00000355481.8 linkuse as main transcript	c.4088C>T	p.Ala1363Val	missense_variant	28/105	1		ENSP00000347667.3	P21817-2
RYR1	ENST00000599547.6 linkuse as main transcript	n.4088C>T		non_coding_transcript_exon_variant	28/80	2		ENSP00000471601.2	M0R127

Frequencies

GnomAD3 genomes

AF:

0.000751

AC:

114

AN:

151758

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00259

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.000289

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000208

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000295

Gnomad OTH

AF:

0.000957

GnomAD3 exomes

AF:

0.000176

AC:

AN:

136656

Hom.:

AF XY:

0.000190

AC XY:

AN XY:

73836

show subpopulations

Gnomad AFR exome

AF:

0.00173

Gnomad AMR exome

AF:

0.0000414

Gnomad ASJ exome

AF:

0.000895

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000187

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000249

GnomAD4 exome

AF:

0.0000904

AC:

126

AN:

1393194

Hom.:

Cov.:

AF XY:

0.0000845

AC XY:

AN XY:

686612

show subpopulations

Gnomad4 AFR exome

AF:

0.00234

Gnomad4 AMR exome

AF:

0.0000847

Gnomad4 ASJ exome

AF:

0.000763

Gnomad4 EAS exome

AF:

0.0000279

Gnomad4 SAS exome

AF:

0.0000638

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000111

Gnomad4 OTH exome

AF:

0.000173

GnomAD4 genome

AF:

0.000751

AC:

114

AN:

151872

Hom.:

Cov.:

AF XY:

0.000687

AC XY:

AN XY:

74216

show subpopulations

Gnomad4 AFR

AF:

0.00258

Gnomad4 AMR

AF:

0.0000655

Gnomad4 ASJ

AF:

0.000289

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000208

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000295

Gnomad4 OTH

AF:

0.000947

Alfa

AF:

0.0000674

Hom.:

Bravo

AF:

0.000895

ExAC

AF:

0.0000646

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:4

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:1

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2024	RYR1: BS2 -
Uncertain significance, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Sep 13, 2016	- -

RYR1-related disorder

Benign:2

Likely benign, no assertion criteria provided	clinical testing	PreventionGenetics, part of Exact Sciences	Jun 10, 2021	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 27, 2024	- -

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Jan 03, 2018

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.081

BayesDel_addAF

Benign

-0.31

BayesDel_noAF

Benign

-0.23

CADD

Benign

DANN

Benign

0.93

DEOGEN2

Benign

0.34

.;T

Eigen

Benign

-0.28

Eigen_PC

Benign

-0.21

FATHMM_MKL

Benign

0.51

LIST_S2

Benign

0.82

T;T

M_CAP

Pathogenic

0.36

MetaRNN

Benign

0.021

T;T

MetaSVM

Uncertain

0.0023

MutationAssessor

Benign

0.0

N;N

PrimateAI

Uncertain

0.54

PROVEAN

Benign

-0.77

N;N

REVEL

Uncertain

0.33

Sift

Benign

0.29

T;T

Polyphen

0.97

D;B

Vest4

0.26

MVP

0.88

MPC

0.31

ClinPred

0.022

GERP RS

4.0

Varity_R

0.084

gMVP

0.38

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