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rs114975624

chr19-38502629-G-Achr19-38502629-G-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_StrongBP6BP7BS1BS2

The NM_000540.3(RYR1):c.7737G>A(p.Val2579=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00166 in 1,613,096 control chromosomes in the GnomAD database, including 43 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0089 ( 21 hom., cov: 28)
Exomes 𝑓: 0.00090 ( 22 hom. )

Consequence

RYR1
NM_000540.3 synonymous

Scores

2

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:9

Conservation

PhyloP100: 0.309
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -14 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=-0.49).
BP6
?
    BP6 - Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation
Variant 19-38502629-G-A is Benign according to our data. Variant chr19-38502629-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 93290.We mark this variant Likely_benign, oryginal submissions are: {Benign=8, Uncertain_significance=1, Likely_benign=1}. Variant chr19-38502629-G-A is described in Lovd as [Benign].
BP7
?
    BP7 - A synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved
Synonymous conserved (PhyloP=0.309 with no splicing effect.
BS1
?
    BS1 - Allele frequency is greater than expected for disorder
Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00891 (1354/152016) while in subpopulation AFR AF= 0.0313 (1296/41442). AF 95% confidence interval is 0.0299. There are 21 homozygotes in gnomad4. There are 661 alleles in male gnomad4 subpopulation. Median coverage is 28. 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 20 AD,AR gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
RYR1NM_000540.3 linkuse as main transcriptc.7737G>A p.Val2579= synonymous_variant 48/106 ENST00000359596.8

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
RYR1ENST00000359596.8 linkuse as main transcriptc.7737G>A p.Val2579= synonymous_variant 48/1065 NM_000540.3 A2P21817-1
RYR1ENST00000355481.8 linkuse as main transcriptc.7737G>A p.Val2579= synonymous_variant 48/1051 P4P21817-2
RYR1ENST00000594335.5 linkuse as main transcriptc.1191G>A p.Val397= synonymous_variant, NMD_transcript_variant 9/491
RYR1ENST00000599547.6 linkuse as main transcriptc.7737G>A p.Val2579= synonymous_variant, NMD_transcript_variant 48/802

Frequencies

GnomAD3 genomes
?
    Genome Aggregation Database, over 76,156 genomes
AF:
0.00890
AC:
1352
AN:
151898
Hom.:
20
Cov.:
28
show subpopulations
Gnomad AFR
AF:
0.0313
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00262
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000588
Gnomad OTH
AF:
0.00671
GnomAD3 exomes
AF:
0.00230
AC:
577
AN:
250508
Hom.:
8
AF XY:
0.00162
AC XY:
220
AN XY:
135652
show subpopulations
Gnomad AFR exome
AF:
0.0317
Gnomad AMR exome
AF:
0.00156
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.0000654
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000265
Gnomad OTH exome
AF:
0.000816
GnomAD4 exome
AF:
0.000901
AC:
1316
AN:
1461080
Hom.:
22
Cov.:
36
AF XY:
0.000802
AC XY:
583
AN XY:
726864
show subpopulations
Gnomad4 AFR exome
AF:
0.0320
Gnomad4 AMR exome
AF:
0.00159
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000928
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000261
Gnomad4 OTH exome
AF:
0.00205
GnomAD4 genome
?
    Genome Aggregation Database, over 76,156 genomes
AF:
0.00891
AC:
1354
AN:
152016
Hom.:
21
Cov.:
28
AF XY:
0.00890
AC XY:
661
AN XY:
74280
show subpopulations
Gnomad4 AFR
AF:
0.0313
Gnomad4 AMR
AF:
0.00262
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000588
Gnomad4 OTH
AF:
0.00664
Alfa
AF:
0.00474
Hom.:
8
Bravo
AF:
0.00961
Asia WGS
AF:
0.00173
AC:
6
AN:
3478
EpiCase
AF:
0.0000545
EpiControl
AF:
0.00

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:1Benign:9
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not specified Benign:3
Benign, criteria provided, single submitterclinical testingGeneDxOct 31, 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 testingEurofins Ntd Llc (ga)Aug 09, 2013- -
Benign, criteria provided, single submitterclinical testingPreventionGenetics, part of Exact SciencesMar 13, 2018- -
not provided Uncertain:1Benign:1
Uncertain significance, criteria provided, single submitterclinical testingGenetic Services Laboratory, University of ChicagoMar 04, 2013- -
Benign, criteria provided, single submitterclinical testingARUP Laboratories, Molecular Genetics and Genomics, ARUP LaboratoriesOct 20, 2023- -
Congenital multicore myopathy with external ophthalmoplegia Benign:1
Benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJan 12, 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 12, 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 testingInvitaeJan 31, 2024- -
Malignant hyperthermia, susceptibility to, 1 Benign:1
Benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJan 12, 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. -
Neuromuscular disease, congenital, with uniform type 1 fiber Benign:1
Likely benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJun 14, 2016- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.49
Cadd
Benign
9.9
Dann
Benign
0.95

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.020
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: rs114975624; hg19: chr19-38993269; API