rs138630815

Positions:

chr19-38440793-C-T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 1P and 9B. PP2BP4_StrongBP6BS1

The NM_000540.3(RYR1):c.94C>T(p.Leu32Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000232 in 1,609,174 control chromosomes in the GnomAD database, including 1 homozygotes. 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 0.0011 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00014 ( 1 hom. )

Consequence

RYR1
NM_000540.3 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 1.18

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 Benign. Variant got -8 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=0.017810881).

BP6

Variant 19-38440793-C-T is Benign according to our data. Variant chr19-38440793-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 195083.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=4, Likely_benign=2}.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00115 (175/152268) while in subpopulation AFR AF= 0.00395 (164/41544). AF 95% confidence interval is 0.00345. There are 0 homozygotes in gnomad4. There are 85 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RYR1	NM_000540.3 linkuse as main transcript	c.94C>T	p.Leu32Phe	missense_variant	2/106	ENST00000359596.8	NP_000531.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RYR1	ENST00000359596.8 linkuse as main transcript	c.94C>T	p.Leu32Phe	missense_variant	2/106	5	NM_000540.3	ENSP00000352608	A2	P21817-1
RYR1	ENST00000355481.8 linkuse as main transcript	c.94C>T	p.Leu32Phe	missense_variant	2/105	1		ENSP00000347667	P4	P21817-2
RYR1	ENST00000599547.6 linkuse as main transcript	c.94C>T	p.Leu32Phe	missense_variant, NMD_transcript_variant	2/80	2		ENSP00000471601

Frequencies

GnomAD3 genomes

AF:

0.00115

AC:

175

AN:

152150

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00396

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000393

Gnomad ASJ

AF:

0.000576

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:

0.000956

GnomAD3 exomes

AF:

0.000248

AC:

AN:

237566

Hom.:

AF XY:

0.000216

AC XY:

AN XY:

129710

show subpopulations

Gnomad AFR exome

AF:

0.00303

Gnomad AMR exome

AF:

0.0000298

Gnomad ASJ exome

AF:

0.000829

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000283

Gnomad OTH exome

AF:

0.000346

GnomAD4 exome

AF:

0.000137

AC:

199

AN:

1456906

Hom.:

Cov.:

AF XY:

0.000101

AC XY:

AN XY:

724536

show subpopulations

Gnomad4 AFR exome

AF:

0.00452

Gnomad4 AMR exome

AF:

0.0000906

Gnomad4 ASJ exome

AF:

0.000732

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000108

Gnomad4 OTH exome

AF:

0.000216

GnomAD4 genome

AF:

0.00115

AC:

175

AN:

152268

Hom.:

Cov.:

AF XY:

0.00114

AC XY:

AN XY:

74460

show subpopulations

Gnomad4 AFR

AF:

0.00395

Gnomad4 AMR

AF:

0.000392

Gnomad4 ASJ

AF:

0.000576

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.000946

Alfa

AF:

0.000279

Hom.:

Bravo

AF:

0.00116

ESP6500AA

AF:

0.00273

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000273

AC:

Asia WGS

AF:

0.000866

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4Benign:4

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:3Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Aug 21, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 23, 2015	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	May 24, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Jul 15, 2019	- -

RYR1-related disorder

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 30, 2024	- -
Likely benign, no assertion criteria provided	clinical testing	PreventionGenetics, part of Exact Sciences	Aug 16, 2022	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). -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

May 16, 2016

- -

Malignant hyperthermia, susceptibility to, 1

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

All of Us Research Program, National Institutes of Health

Sep 23, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.20

BayesDel_addAF

Benign

-0.26

BayesDel_noAF

Benign

-0.14

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.71

.;D

Eigen

Uncertain

0.33

Eigen_PC

Uncertain

0.34

FATHMM_MKL

Benign

0.67

LIST_S2

Uncertain

0.95

D;D

M_CAP

Pathogenic

0.70

MetaRNN

Benign

0.018

T;T

MetaSVM

Uncertain

0.30

MutationAssessor

Benign

1.2

L;L

MutationTaster

Benign

0.94

N;N;N

PrimateAI

Uncertain

0.62

PROVEAN

Benign

-1.5

N;N

REVEL

Uncertain

0.39

Sift

Benign

0.071

T;T

Polyphen

0.99

D;D

Vest4

0.36

MVP

0.94

MPC

0.95

ClinPred

0.033

GERP RS

3.8

Varity_R

0.13

gMVP

0.30

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