rs35021937

Positions:

• chr19-38489251-A-G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_000540.3(RYR1):​c.5622A>G​(p.Glu1874Glu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0288 in 1,613,096 control chromosomes in the GnomAD database, including 842 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.022 (67 hom., cov: 32)
  • Exomes 𝑓: 0.029 (775 hom.)
• Consequence: RYR1 NM_000540.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:14
• Conservation: PhyloP100: -0.165

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.52).
• BP6: Variant 19-38489251-A-G is Benign according to our data. Variant chr19-38489251-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 159853.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-38489251-A-G is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.165 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0218 (3319/152204) while in subpopulation NFE AF= 0.0276 (1875/67994). AF 95% confidence interval is 0.0265. There are 67 homozygotes in gnomad4. There are 1667 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 67 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RYR1	NM_000540.3	c.5622A>G	p.Glu1874Glu	synonymous_variant	35/106	ENST00000359596.8	NP_000531.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RYR1	ENST00000359596.8	c.5622A>G	p.Glu1874Glu	synonymous_variant	35/106	5	NM_000540.3	ENSP00000352608.2
RYR1	ENST00000355481.8	c.5622A>G	p.Glu1874Glu	synonymous_variant	35/105	1		ENSP00000347667.3
RYR1	ENST00000599547.6	n.5622A>G		non_coding_transcript_exon_variant	35/80	2		ENSP00000471601.2

Frequencies

GnomAD3 genomes AF: 0.0218 AC: 3320 AN: 152086 Hom.: 67 Cov.: 32

Gnomad AFR AF: 0.0108

Gnomad AMI AF: 0.0352

Gnomad AMR AF: 0.00767

Gnomad ASJ AF: 0.0150

Gnomad EAS AF: 0.000578

Gnomad SAS AF: 0.00747

Gnomad FIN AF: 0.0685

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0276

Gnomad OTH AF: 0.0149

GnomAD3 exomes AF: 0.0225 AC: 5587 AN: 248644 Hom.: 110 AF XY: 0.0225 AC XY: 3030 AN XY: 134634

Gnomad AFR exome AF: 0.00831

Gnomad AMR exome AF: 0.00925

Gnomad ASJ exome AF: 0.0159

Gnomad EAS exome AF: 0.000544

Gnomad SAS exome AF: 0.00899

Gnomad FIN exome AF: 0.0658

Gnomad NFE exome AF: 0.0282

Gnomad OTH exome AF: 0.0211

GnomAD4 exome AF: 0.0295 AC: 43064 AN: 1460892 Hom.: 775 Cov.: 32 AF XY: 0.0288 AC XY: 20955 AN XY: 726822

Gnomad4 AFR exome AF: 0.0105

Gnomad4 AMR exome AF: 0.00870

Gnomad4 ASJ exome AF: 0.0161

Gnomad4 EAS exome AF: 0.000353

Gnomad4 SAS exome AF: 0.00848

Gnomad4 FIN exome AF: 0.0629

Gnomad4 NFE exome AF: 0.0326

Gnomad4 OTH exome AF: 0.0249

GnomAD4 genome AF: 0.0218 AC: 3319 AN: 152204 Hom.: 67 Cov.: 32 AF XY: 0.0224 AC XY: 1667 AN XY: 74434

Gnomad4 AFR AF: 0.0108

Gnomad4 AMR AF: 0.00766

Gnomad4 ASJ AF: 0.0150

Gnomad4 EAS AF: 0.000580

Gnomad4 SAS AF: 0.00726

Gnomad4 FIN AF: 0.0685

Gnomad4 NFE AF: 0.0276

Gnomad4 OTH AF: 0.0147

Alfa AF: 0.0252 Hom.: 77

Bravo AF: 0.0177

Asia WGS AF: 0.00577 AC: 20 AN: 3478

EpiCase AF: 0.0245

EpiControl AF: 0.0256

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:14

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:7

Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 29, 2016	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. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Mar 06, 2018	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 08, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 08, 2013	- -
Benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

Malignant hyperthermia, susceptibility to, 1 Benign:2

Benign, 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 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. -
Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Aug 17, 2022	- -

Congenital multicore myopathy with external ophthalmoplegia Benign:1

Benign, 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 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 submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

not provided Benign:1

Likely benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

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

- -

Central core myopathy Benign:1

Benign, 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 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.52
CADD	Benign	4.2
DANN	Benign	0.79

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: rs35021937; hg19: chr19-38979891; COSMIC: COSV62097629;