Variant rs75563090 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.6548+43G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.036 in 1,609,796 control chromosomes in the GnomAD database, including 1,369 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.039 ( 173 hom., cov: 31)

Exomes 𝑓: 0.036 ( 1196 hom. )

Consequence

RYR1
NM_000540.3 intron

Scores

Clinical Significance

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

Conservation

PhyloP100: -1.60

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=-0.92).

BP6

Variant 19-38494668-G-A is Benign according to our data. Variant chr19-38494668-G-A is described in ClinVar as [Benign]. Clinvar id is 256535.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0385 (5863/152110) while in subpopulation NFE AF= 0.0405 (2750/67974). AF 95% confidence interval is 0.0392. There are 173 homozygotes in gnomad4. There are 3102 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 173 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RYR1	NM_000540.3 linkuse as main transcript	c.6548+43G>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.6548+43G>A	intron_variant	5	NM_000540.3	ENSP00000352608	A2	P21817-1
RYR1	ENST00000355481.8 linkuse as main transcript	c.6548+43G>A	intron_variant	1		ENSP00000347667	P4	P21817-2
RYR1	ENST00000599547.6 linkuse as main transcript	c.6548+43G>A	intron_variant, NMD_transcript_variant	2		ENSP00000471601

Frequencies

GnomAD3 genomes

AF:

0.0386

AC:

5860

AN:

151992

Hom.:

173

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0230

Gnomad AMI

AF:

0.0352

Gnomad AMR

AF:

0.0282

Gnomad ASJ

AF:

0.0548

Gnomad EAS

AF:

0.0148

Gnomad SAS

AF:

0.0182

Gnomad FIN

AF:

0.117

Gnomad MID

AF:

0.0538

Gnomad NFE

AF:

0.0405

Gnomad OTH

AF:

0.0394

GnomAD3 exomes

AF:

0.0392

AC:

9667

AN:

246584

Hom.:

320

AF XY:

0.0386

AC XY:

5182

AN XY:

134300

show subpopulations

Gnomad AFR exome

AF:

0.0243

Gnomad AMR exome

AF:

0.0185

Gnomad ASJ exome

AF:

0.0502

Gnomad EAS exome

AF:

0.0134

Gnomad SAS exome

AF:

0.0220

Gnomad FIN exome

AF:

0.121

Gnomad NFE exome

AF:

0.0399

Gnomad OTH exome

AF:

0.0431

GnomAD4 exome

AF:

0.0357

AC:

52065

AN:

1457686

Hom.:

1196

Cov.:

AF XY:

0.0355

AC XY:

25755

AN XY:

725364

show subpopulations

Gnomad4 AFR exome

AF:

0.0250

Gnomad4 AMR exome

AF:

0.0196

Gnomad4 ASJ exome

AF:

0.0522

Gnomad4 EAS exome

AF:

0.00847

Gnomad4 SAS exome

AF:

0.0216

Gnomad4 FIN exome

AF:

0.114

Gnomad4 NFE exome

AF:

0.0347

Gnomad4 OTH exome

AF:

0.0346

GnomAD4 genome

AF:

0.0385

AC:

5863

AN:

152110

Hom.:

173

Cov.:

AF XY:

0.0417

AC XY:

3102

AN XY:

74370

show subpopulations

Gnomad4 AFR

AF:

0.0231

Gnomad4 AMR

AF:

0.0281

Gnomad4 ASJ

AF:

0.0548

Gnomad4 EAS

AF:

0.0148

Gnomad4 SAS

AF:

0.0187

Gnomad4 FIN

AF:

0.117

Gnomad4 NFE

AF:

0.0405

Gnomad4 OTH

AF:

0.0390

Alfa

AF:

0.0407

Hom.:

Bravo

AF:

0.0321

Asia WGS

AF:

0.0210

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 26, 2018	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 23, 2013

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.92

CADD

Benign

0.43

DANN

Benign

0.56

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