Variant 19-38453061-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_000540.3(RYR1):c.1440+47G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000336 in 1,597,698 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.00047 ( 1 hom., cov: 32)

Exomes 𝑓: 0.00032 ( 2 hom. )

Consequence

RYR1
NM_000540.3 intron

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 2.24

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 -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.76).

BP6

Variant 19-38453061-G-A is Benign according to our data. Variant chr19-38453061-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 256444.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.000473 (72/152158) while in subpopulation EAS AF= 0.0108 (56/5172). AF 95% confidence interval is 0.00856. There are 1 homozygotes in gnomad4. There are 36 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAdExome4 at 2 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RYR1	NM_000540.3 linkuse as main transcript	c.1440+47G>A		intron_variant		ENST00000359596.8	NP_000531.2

Ensembl

Gene	Transcript	HGVSc	Effect	TSL	MANE	Protein	Appris	UniProt
RYR1	ENST00000359596.8 linkuse as main transcript	c.1440+47G>A	intron_variant	5	NM_000540.3	ENSP00000352608	A2	P21817-1
RYR1	ENST00000355481.8 linkuse as main transcript	c.1440+47G>A	intron_variant	1		ENSP00000347667	P4	P21817-2
RYR1	ENST00000599547.6 linkuse as main transcript	c.1440+47G>A	intron_variant, NMD_transcript_variant	2		ENSP00000471601

Frequencies

GnomAD3 genomes

AF:

0.000480

AC:

AN:

152040

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000145

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.0110

Gnomad SAS

AF:

0.000623

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00191

GnomAD3 exomes

AF:

0.000900

AC:

199

AN:

221058

Hom.:

AF XY:

0.000847

AC XY:

103

AN XY:

121570

show subpopulations

Gnomad AFR exome

AF:

0.0000801

Gnomad AMR exome

AF:

0.0000307

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0113

Gnomad SAS exome

AF:

0.0000692

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00108

GnomAD4 exome

AF:

0.000322

AC:

465

AN:

1445540

Hom.:

Cov.:

AF XY:

0.000287

AC XY:

206

AN XY:

718546

show subpopulations

Gnomad4 AFR exome

AF:

0.000181

Gnomad4 AMR exome

AF:

0.0000230

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00833

Gnomad4 SAS exome

AF:

0.000201

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000363

Gnomad4 OTH exome

AF:

0.00184

GnomAD4 genome

AF:

0.000473

AC:

AN:

152158

Hom.:

Cov.:

AF XY:

0.000484

AC XY:

AN XY:

74392

show subpopulations

Gnomad4 AFR

AF:

0.000145

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.0108

Gnomad4 SAS

AF:

0.000623

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00189

Alfa

AF:

0.000342

Hom.:

Bravo

AF:

0.000691

Asia WGS

AF:

0.00693

AC:

AN:

3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 06, 2018	- -

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.76

CADD

Benign

8.9

DANN

Benign

0.95

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