dbSNP rs908644: RYR1:c.10825-218C>G (chr19-38528088-C-G) – ACMG Classification: Benign (-20 pts)

Variant summary

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

The NM_000540.3(RYR1):c.10825-218C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.179 in 632,186 control chromosomes in the GnomAD database, including 11,882 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.22 ( 4233 hom., cov: 31)

Exomes 𝑓: 0.17 ( 7649 hom. )

Consequence

RYR1
NM_000540.3 intron

Scores

Clinical Significance

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

Conservation

PhyloP100: -0.204

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:

ENSG00000269445 (HGNC:):

ENSG00000269445 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=-0.97).

BP6

Variant 19-38528088-C-G is Benign according to our data. Variant chr19-38528088-C-G is described in ClinVar as [Benign]. Clinvar id is 133000.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-38528088-C-G is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.356 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RYR1	NM_000540.3 link	c.10825-218C>G		intron_variant	Intron 73 of 105	ENST00000359596.8	NP_000531.2	P21817-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RYR1	ENST00000359596.8 link	c.10825-218C>G		intron_variant	Intron 73 of 105	5	NM_000540.3	ENSP00000352608.2		P21817-1

Frequencies

GnomAD3 genomes

AF:

0.216

AC:

32756

AN:

151604

Hom.:

4215

Cov.:

show subpopulations

Gnomad AFR

AF:

0.360

Gnomad AMI

AF:

0.249

Gnomad AMR

AF:

0.182

Gnomad ASJ

AF:

0.178

Gnomad EAS

AF:

0.176

Gnomad SAS

AF:

0.284

Gnomad FIN

AF:

0.162

Gnomad MID

AF:

0.199

Gnomad NFE

AF:

0.145

Gnomad OTH

AF:

0.211

GnomAD3 exomes

AF:

0.185

AC:

13159

AN:

71204

Hom.:

1473

AF XY:

0.183

AC XY:

6726

AN XY:

36738

show subpopulations

Gnomad AFR exome

AF:

0.372

Gnomad AMR exome

AF:

0.142

Gnomad ASJ exome

AF:

0.177

Gnomad EAS exome

AF:

0.164

Gnomad SAS exome

AF:

0.289

Gnomad FIN exome

AF:

0.155

Gnomad NFE exome

AF:

0.142

Gnomad OTH exome

AF:

0.184

GnomAD4 exome

AF:

0.168

AC:

80532

AN:

480464

Hom.:

7649

Cov.:

AF XY:

0.172

AC XY:

43965

AN XY:

255524

show subpopulations

Gnomad4 AFR exome

AF:

0.372

Gnomad4 AMR exome

AF:

0.148

Gnomad4 ASJ exome

AF:

0.180

Gnomad4 EAS exome

AF:

0.148

Gnomad4 SAS exome

AF:

0.269

Gnomad4 FIN exome

AF:

0.164

Gnomad4 NFE exome

AF:

0.143

Gnomad4 OTH exome

AF:

0.177

GnomAD4 genome

AF:

0.216

AC:

32824

AN:

151722

Hom.:

4233

Cov.:

AF XY:

0.220

AC XY:

16302

AN XY:

74178

show subpopulations

Gnomad4 AFR

AF:

0.360

Gnomad4 AMR

AF:

0.181

Gnomad4 ASJ

AF:

0.178

Gnomad4 EAS

AF:

0.175

Gnomad4 SAS

AF:

0.284

Gnomad4 FIN

AF:

0.162

Gnomad4 NFE

AF:

0.145

Gnomad4 OTH

AF:

0.215

Alfa

AF:

0.178

Hom.:

388

Bravo

AF:

0.220

Asia WGS

AF:

0.286

AC:

995

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

RYR1 database

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Jun 26, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.97

CADD

Benign

1.7

DANN

Benign

0.60

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