Variant 19-38458323-C-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.2167+31C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.199 in 1,603,514 control chromosomes in the GnomAD database, including 33,357 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.17 ( 2522 hom., cov: 31)

Exomes 𝑓: 0.20 ( 30835 hom. )

Consequence

RYR1
NM_000540.3 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3O:1

Conservation

PhyloP100: 0.168

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

Computational evidence support a benign effect (BayesDel_noAF=-0.72).

BP6

Variant 19-38458323-C-G is Benign according to our data. Variant chr19-38458323-C-G is described in ClinVar as [Benign]. Clinvar id is 133112.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-38458323-C-G is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.348 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RYR1	NM_000540.3 linkuse as main transcript	c.2167+31C>G		intron_variant		ENST00000359596.8

Ensembl

Gene	Transcript	HGVSc	Effect	TSL	MANE	Appris	UniProt
RYR1	ENST00000359596.8 linkuse as main transcript	c.2167+31C>G	intron_variant	5	NM_000540.3	A2	P21817-1
RYR1	ENST00000355481.8 linkuse as main transcript	c.2167+31C>G	intron_variant	1		P4	P21817-2
RYR1	ENST00000599547.6 linkuse as main transcript	c.2167+31C>G	intron_variant, NMD_transcript_variant	2

Frequencies

GnomAD3 genomes

AF:

0.168

AC:

25484

AN:

151984

Hom.:

2524

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0787

Gnomad AMI

AF:

0.129

Gnomad AMR

AF:

0.183

Gnomad ASJ

AF:

0.177

Gnomad EAS

AF:

0.363

Gnomad SAS

AF:

0.281

Gnomad FIN

AF:

0.203

Gnomad MID

AF:

0.0949

Gnomad NFE

AF:

0.191

Gnomad OTH

AF:

0.160

GnomAD3 exomes

AF:

0.209

AC:

51225

AN:

244530

Hom.:

5965

AF XY:

0.212

AC XY:

28306

AN XY:

133402

show subpopulations

Gnomad AFR exome

AF:

0.0765

Gnomad AMR exome

AF:

0.199

Gnomad ASJ exome

AF:

0.182

Gnomad EAS exome

AF:

0.361

Gnomad SAS exome

AF:

0.267

Gnomad FIN exome

AF:

0.209

Gnomad NFE exome

AF:

0.193

Gnomad OTH exome

AF:

0.195

GnomAD4 exome

AF:

0.202

AC:

292883

AN:

1451412

Hom.:

30835

Cov.:

AF XY:

0.203

AC XY:

146978

AN XY:

722690

show subpopulations

Gnomad4 AFR exome

AF:

0.0699

Gnomad4 AMR exome

AF:

0.199

Gnomad4 ASJ exome

AF:

0.187

Gnomad4 EAS exome

AF:

0.314

Gnomad4 SAS exome

AF:

0.261

Gnomad4 FIN exome

AF:

0.211

Gnomad4 NFE exome

AF:

0.198

Gnomad4 OTH exome

AF:

0.197

GnomAD4 genome

AF:

0.168

AC:

25486

AN:

152102

Hom.:

2522

Cov.:

AF XY:

0.172

AC XY:

12813

AN XY:

74344

show subpopulations

Gnomad4 AFR

AF:

0.0787

Gnomad4 AMR

AF:

0.182

Gnomad4 ASJ

AF:

0.177

Gnomad4 EAS

AF:

0.362

Gnomad4 SAS

AF:

0.281

Gnomad4 FIN

AF:

0.203

Gnomad4 NFE

AF:

0.191

Gnomad4 OTH

AF:

0.164

Alfa

AF:

0.179

Hom.:

459

Bravo

AF:

0.162

Asia WGS

AF:

0.348

AC:

1209

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:3Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2Other:1

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 19, 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)	-	- -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 18, 2013

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.72

CADD

Benign

DANN

Benign

0.74

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