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GeneBe

rs78350770

chr19-38529064-A-G

Variant summary

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

The NM_000540.3(RYR1):c.11141+7A>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00125 in 1,612,862 control chromosomes in the GnomAD database, including 38 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0018 ( 8 hom., cov: 32)
Exomes 𝑓: 0.0012 ( 30 hom. )

Consequence

RYR1
NM_000540.3 splice_region, intron

Scores

2
Splicing: ADA: 0.0001367
2

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11

Conservation

PhyloP100: -0.277
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]

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4
?
    BP4 - Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc.)
Computational evidence support a benign effect (BayesDel_noAF=-0.79).
BP6
?
    BP6 - Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation
Variant 19-38529064-A-G is Benign according to our data. Variant chr19-38529064-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 159829.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-38529064-A-G is described in Lovd as [Likely_benign].
BS1
?
    BS1 - Allele frequency is greater than expected for disorder
Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00178 (270/151928) while in subpopulation EAS AF= 0.0437 (224/5126). AF 95% confidence interval is 0.039. There are 8 homozygotes in gnomad4. There are 144 alleles in male gnomad4 subpopulation. This position pass quality control queck.
BS2
?
    BS2 - Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age
High Homozygotes in GnomAd at 7 AD,AR gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
RYR1NM_000540.3 linkuse as main transcriptc.11141+7A>G splice_region_variant, intron_variant ENST00000359596.8

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
RYR1ENST00000359596.8 linkuse as main transcriptc.11141+7A>G splice_region_variant, intron_variant 5 NM_000540.3 A2P21817-1

Frequencies

GnomAD3 genomes
?
    Genome Aggregation Database, over 76,156 genomes
AF:
0.00176
AC:
267
AN:
151810
Hom.:
7
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.000581
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000459
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.0430
Gnomad SAS
AF:
0.00125
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000589
Gnomad OTH
AF:
0.00239
GnomAD3 exomes
AF:
0.00385
AC:
955
AN:
248368
Hom.:
20
AF XY:
0.00372
AC XY:
500
AN XY:
134500
show subpopulations
Gnomad AFR exome
AF:
0.000495
Gnomad AMR exome
AF:
0.000319
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.0477
Gnomad SAS exome
AF:
0.00131
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000540
Gnomad OTH exome
AF:
0.00229
GnomAD4 exome
AF:
0.00120
AC:
1753
AN:
1460934
Hom.:
30
Cov.:
32
AF XY:
0.00125
AC XY:
911
AN XY:
726752
show subpopulations
Gnomad4 AFR exome
AF:
0.000239
Gnomad4 AMR exome
AF:
0.000358
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0347
Gnomad4 SAS exome
AF:
0.00131
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000468
Gnomad4 OTH exome
AF:
0.00308
GnomAD4 genome
?
    Genome Aggregation Database, over 76,156 genomes
AF:
0.00178
AC:
270
AN:
151928
Hom.:
8
Cov.:
32
AF XY:
0.00194
AC XY:
144
AN XY:
74234
show subpopulations
Gnomad4 AFR
AF:
0.000579
Gnomad4 AMR
AF:
0.000459
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.0437
Gnomad4 SAS
AF:
0.00125
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000589
Gnomad4 OTH
AF:
0.00237
Alfa
AF:
0.000402
Hom.:
0
Bravo
AF:
0.00217
Asia WGS
AF:
0.0140
AC:
50
AN:
3478
EpiCase
AF:
0.00
EpiControl
AF:
0.000178

ClinVar

Significance: Benign/Likely benign
Submissions summary: Benign:11
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not specified Benign:5
Benign, criteria provided, single submitterclinical testingGeneDxOct 21, 2016This 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. -
Benign, criteria provided, single submitterclinical testingPreventionGenetics, part of Exact SciencesSep 25, 2017- -
Benign, criteria provided, single submitterclinical testingGenetic Services Laboratory, University of ChicagoFeb 08, 2013- -
Benign, criteria provided, single submitterclinical testingEurofins Ntd Llc (ga)Nov 10, 2014- -
Benign, criteria provided, single submitterclinical testingAthena DiagnosticsFeb 17, 2020- -
Congenital multicore myopathy with external ophthalmoplegia Benign:1
Benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJan 13, 2018This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Central core myopathy Benign:1
Benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJan 13, 2018This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Malignant hyperthermia, susceptibility to, 1 Benign:1
Benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJan 13, 2018This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
RYR1-related disorder Benign:1
Benign, criteria provided, single submitterclinical testingInvitaeFeb 01, 2024- -
Neuromuscular disease, congenital, with uniform type 1 fiber Benign:1
Likely benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJun 14, 2016- -
Congenital myopathy with fiber type disproportion;C0751951:Central core myopathy;C1840365:King Denborough syndrome;C1850674:Congenital multicore myopathy with external ophthalmoplegia;C2930980:Malignant hyperthermia, susceptibility to, 1 Benign:1
Likely benign, criteria provided, single submitterclinical testingFulgent Genetics, Fulgent GeneticsNov 04, 2021- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.79
Cadd
Benign
1.6
Dann
Benign
0.72

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Benign
0.00014
dbscSNV1_RF
Benign
0.028
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.

Other links and lift over

dbSNP: rs78350770; hg19: chr19-39019704; API