rs193922854

Positions:

• chr19-38565213-G-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BS1 BS2

The NM_000540.3(RYR1):​c.12879G>C​(p.Ala4293Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0153 in 994,122 control chromosomes in the GnomAD database, including 126 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 0.0083 (7 hom., cov: 32)
  • Exomes 𝑓: 0.016 (119 hom.)
• Consequence: RYR1 NM_000540.3 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6 B:9 O:1
• Conservation: PhyloP100: 0.0160

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]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 19-38565213-G-C is Benign according to our data. Variant chr19-38565213-G-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 93249.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=6, not_provided=1, Benign=2}. Variant chr19-38565213-G-C is described in Lovd as [Likely_benign]. Variant chr19-38565213-G-C is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=0.016 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00833 (1223/146758) while in subpopulation NFE AF= 0.0135 (892/65924). AF 95% confidence interval is 0.0128. There are 7 homozygotes in gnomad4. There are 562 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 7 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RYR1	NM_000540.3	c.12879G>C	p.Ala4293Ala	synonymous_variant	91/106	ENST00000359596.8	NP_000531.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RYR1	ENST00000359596.8	c.12879G>C	p.Ala4293Ala	synonymous_variant	91/106	5	NM_000540.3	ENSP00000352608.2

Frequencies

GnomAD3 genomes AF: 0.00834 AC: 1223 AN: 146652 Hom.: 7 Cov.: 32

Gnomad AFR AF: 0.00315

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00264

Gnomad ASJ AF: 0.000295

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00166

Gnomad FIN AF: 0.0160

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0135

Gnomad OTH AF: 0.00941

GnomAD3 exomes AF: 0.00654 AC: 2 AN: 306 Hom.: 0 AF XY: 0.0114 AC XY: 2 AN XY: 176

Gnomad AMR exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00690

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0165 AC: 13947 AN: 847364 Hom.: 119 Cov.: 30 AF XY: 0.0165 AC XY: 6483 AN XY: 393092

Gnomad4 AFR exome AF: 0.00181

Gnomad4 AMR exome AF: 0.00937

Gnomad4 ASJ exome AF: 0.00111

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00149

Gnomad4 FIN exome AF: 0.0149

Gnomad4 NFE exome AF: 0.0176

Gnomad4 OTH exome AF: 0.0103

GnomAD4 genome AF: 0.00833 AC: 1223 AN: 146758 Hom.: 7 Cov.: 32 AF XY: 0.00787 AC XY: 562 AN XY: 71442

Gnomad4 AFR AF: 0.00315

Gnomad4 AMR AF: 0.00264

Gnomad4 ASJ AF: 0.000295

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00166

Gnomad4 FIN AF: 0.0160

Gnomad4 NFE AF: 0.0135

Gnomad4 OTH AF: 0.00930

Alfa AF: 0.0112 Hom.: 1

Bravo AF: 0.00761

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:6 Benign:9 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:4 Other:1

Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 11, 2016	- -
not provided, no classification provided	literature only	Leiden Muscular Dystrophy (RYR1)	-	- -
Likely benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2024	RYR1: BP4, BP7, BS1, BS2 -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

Malignant hyperthermia, susceptibility to, 1 Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	This 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -
Uncertain significance, criteria provided, single submitter	clinical testing	Knight Diagnostic Laboratories, Oregon Health and Sciences University	Sep 26, 2015	- -

not specified Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Mar 15, 2016	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 12, 2017	This 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. -

RYR1-related disorder Benign:2

Benign, no assertion criteria provided	clinical testing	PreventionGenetics, part of Exact Sciences	Jul 25, 2021	This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

Congenital multicore myopathy with external ophthalmoplegia Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Malignant hyperthermia of anesthesia Uncertain:1

Uncertain significance, criteria provided, single submitter

research

CSER _CC_NCGL, University of Washington

Jan 01, 2016

- -

Central core myopathy Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Neuromuscular disease, congenital, with uniform type 1 fiber Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	1.1
DANN	Benign	0.52

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

Other links and lift over

dbSNP: rs193922854; hg19: chr19-39055853;