Variant 19-38459089-T-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000540.3(RYR1):c.2168-57T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.634 in 1,422,274 control chromosomes in the GnomAD database, including 289,928 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). There are indicators that this mutation may affect the branch point..

Frequency

Genomes: 𝑓 0.62 ( 30138 hom., cov: 31)

Exomes 𝑓: 0.64 ( 259790 hom. )

Consequence

RYR1
NM_000540.3 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2O:1

Conservation

PhyloP100: 0.224

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:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

This place is a probable branch point but likely benign (scored 1 / 10). Computational evidence support a benign effect (BayesDel_noAF=-0.81).

BP6

Variant 19-38459089-T-G is Benign according to our data. Variant chr19-38459089-T-G is described in ClinVar as [Benign]. Clinvar id is 133113.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-38459089-T-G is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.678 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RYR1	NM_000540.3 link	c.2168-57T>G		intron_variant		ENST00000359596.8	NP_000531.2	P21817-1

Ensembl

Gene	Transcript	HGVSc	Effect	TSL	MANE	Protein	UniProt
RYR1	ENST00000359596.8 link	c.2168-57T>G	intron_variant	5	NM_000540.3	ENSP00000352608.2	P21817-1
RYR1	ENST00000355481.8 link	c.2168-57T>G	intron_variant	1		ENSP00000347667.3	P21817-2
RYR1	ENST00000599547.6 link	n.2168-57T>G	intron_variant	2		ENSP00000471601.2	M0R127

Frequencies

GnomAD3 genomes

AF:

0.624

AC:

94747

AN:

151896

Hom.:

30125

Cov.:

show subpopulations

Gnomad AFR

AF:

0.536

Gnomad AMI

AF:

0.796

Gnomad AMR

AF:

0.689

Gnomad ASJ

AF:

0.670

Gnomad EAS

AF:

0.594

Gnomad SAS

AF:

0.419

Gnomad FIN

AF:

0.709

Gnomad MID

AF:

0.703

Gnomad NFE

AF:

0.661

Gnomad OTH

AF:

0.637

GnomAD4 exome

AF:

0.636

AC:

807319

AN:

1270260

Hom.:

259790

AF XY:

0.630

AC XY:

404132

AN XY:

641694

show subpopulations

Gnomad4 AFR exome

AF:

0.528

Gnomad4 AMR exome

AF:

0.687

Gnomad4 ASJ exome

AF:

0.664

Gnomad4 EAS exome

AF:

0.647

Gnomad4 SAS exome

AF:

0.436

Gnomad4 FIN exome

AF:

0.694

Gnomad4 NFE exome

AF:

0.649

Gnomad4 OTH exome

AF:

0.639

GnomAD4 genome

AF:

0.624

AC:

94796

AN:

152014

Hom.:

30138

Cov.:

AF XY:

0.621

AC XY:

46116

AN XY:

74310

show subpopulations

Gnomad4 AFR

AF:

0.535

Gnomad4 AMR

AF:

0.690

Gnomad4 ASJ

AF:

0.670

Gnomad4 EAS

AF:

0.595

Gnomad4 SAS

AF:

0.419

Gnomad4 FIN

AF:

0.709

Gnomad4 NFE

AF:

0.661

Gnomad4 OTH

AF:

0.632

Alfa

AF:

0.652

Hom.:

9755

Bravo

AF:

0.625

Asia WGS

AF:

0.453

AC:

1578

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:2Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2Other:1

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 14, 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. -
not provided, no classification provided	literature only	Leiden Muscular Dystrophy (RYR1)	-	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.81

CADD

Benign

4.1

DANN

Benign

0.72

BranchPoint Hunter

1.0

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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