rs77310009

chr19-38499974-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000540.3(RYR1):c.7281C>T(p.Ala2427=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00532 in 1,614,144 control chromosomes in the GnomAD database, including 230 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0083 (32 hom., cov: 31)
  • Exomes 𝑓: 0.0050 (198 hom.)
• Consequence: RYR1 NM_000540.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: -3.77

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=-0.68).
• BP6: Variant 19-38499974-C-T is Benign according to our data. Variant chr19-38499974-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 159857.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-38499974-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-3.77 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0618 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RYR1	NM_000540.3	c.7281C>T	p.Ala2427=	synonymous_variant	45/106	ENST00000359596.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RYR1	ENST00000359596.8	c.7281C>T	p.Ala2427=	synonymous_variant	45/106	5	NM_000540.3	A2
RYR1	ENST00000355481.8	c.7281C>T	p.Ala2427=	synonymous_variant	45/105	1		P4
RYR1	ENST00000594335.5	c.735C>T	p.Ala245=	synonymous_variant, NMD_transcript_variant	6/49	1
RYR1	ENST00000599547.6	c.7281C>T	p.Ala2427=	synonymous_variant, NMD_transcript_variant	45/80	2

Frequencies

GnomAD3 genomes AF: 0.00835 AC: 1270 AN: 152166 Hom.: 32 Cov.: 31

Gnomad AFR AF: 0.00429

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0374

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.0677

Gnomad SAS AF: 0.0257

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000265

Gnomad OTH AF: 0.0110

GnomAD3 exomes AF: 0.0136 AC: 3414 AN: 251370 Hom.: 93 AF XY: 0.0121 AC XY: 1648 AN XY: 135882

Gnomad AFR exome AF: 0.00375

Gnomad AMR exome AF: 0.0440

Gnomad ASJ exome AF: 0.00198

Gnomad EAS exome AF: 0.0596

Gnomad SAS exome AF: 0.0202

Gnomad FIN exome AF: 0.000277

Gnomad NFE exome AF: 0.000325

Gnomad OTH exome AF: 0.00880

GnomAD4 exome AF: 0.00501 AC: 7319 AN: 1461860 Hom.: 198 Cov.: 36 AF XY: 0.00527 AC XY: 3829 AN XY: 727232

Gnomad4 AFR exome AF: 0.00388

Gnomad4 AMR exome AF: 0.0411

Gnomad4 ASJ exome AF: 0.00184

Gnomad4 EAS exome AF: 0.0728

Gnomad4 SAS exome AF: 0.0201

Gnomad4 FIN exome AF: 0.000356

Gnomad4 NFE exome AF: 0.000177

Gnomad4 OTH exome AF: 0.00748

GnomAD4 genome AF: 0.00834 AC: 1270 AN: 152284 Hom.: 32 Cov.: 31 AF XY: 0.00984 AC XY: 733 AN XY: 74456

Gnomad4 AFR AF: 0.00428

Gnomad4 AMR AF: 0.0372

Gnomad4 ASJ AF: 0.00115

Gnomad4 EAS AF: 0.0676

Gnomad4 SAS AF: 0.0253

Gnomad4 FIN AF: 0.0000941

Gnomad4 NFE AF: 0.000265

Gnomad4 OTH AF: 0.0137

Alfa AF: 0.00181 Hom.: 1

Bravo AF: 0.0109

Asia WGS AF: 0.0530 AC: 185 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.000356

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Dec 19, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 22, 2014	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 07, 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. -

Malignant hyperthermia, susceptibility to, 1 Benign:2

Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Sep 16, 2022	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 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. -

Congenital multicore myopathy with external ophthalmoplegia Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 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. -

Central core myopathy Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

not provided Benign:1

Likely benign, no assertion criteria provided

clinical testing

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

-

- -

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

- -

RYR1-Related Disorders Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.68
Cadd	Benign	1.7
Dann	Benign	0.57

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: rs77310009; hg19: chr19-38990614; COSMIC: COSV62088367;