rs2234709

Positions:

• chr19-38500036-C-A
• chr19-38500036-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000540.3(RYR1):​c.7323+20C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0568 in 1,609,466 control chromosomes in the GnomAD database, including 3,045 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.067 (374 hom., cov: 32)
  • Exomes 𝑓: 0.056 (2671 hom.)
• Consequence: RYR1 NM_000540.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5 O:1
• Conservation: PhyloP100: -0.0980

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BP6: Variant 19-38500036-C-A is Benign according to our data. Variant chr19-38500036-C-A is described in ClinVar as [Benign]. Clinvar id is 93286.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-38500036-C-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.131 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RYR1	NM_000540.3	c.7323+20C>A		intron_variant		ENST00000359596.8	NP_000531.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RYR1	ENST00000359596.8	c.7323+20C>A		intron_variant		5	NM_000540.3	ENSP00000352608	A2
RYR1	ENST00000355481.8	c.7323+20C>A		intron_variant		1		ENSP00000347667	P4
RYR1	ENST00000594335.5	c.775+20C>A		intron_variant, NMD_transcript_variant		1		ENSP00000470927
RYR1	ENST00000599547.6	c.7323+20C>A		intron_variant, NMD_transcript_variant		2		ENSP00000471601

Frequencies

GnomAD3 genomes AF: 0.0665 AC: 10124 AN: 152152 Hom.: 372 Cov.: 32

Gnomad AFR AF: 0.0578

Gnomad AMI AF: 0.0208

Gnomad AMR AF: 0.0658

Gnomad ASJ AF: 0.0956

Gnomad EAS AF: 0.140

Gnomad SAS AF: 0.0552

Gnomad FIN AF: 0.122

Gnomad MID AF: 0.0823

Gnomad NFE AF: 0.0575

Gnomad OTH AF: 0.0750

GnomAD3 exomes AF: 0.0693 AC: 17315 AN: 249882 Hom.: 715 AF XY: 0.0688 AC XY: 9305 AN XY: 135206

Gnomad AFR exome AF: 0.0610

Gnomad AMR exome AF: 0.0468

Gnomad ASJ exome AF: 0.0918

Gnomad EAS exome AF: 0.138

Gnomad SAS exome AF: 0.0553

Gnomad FIN exome AF: 0.126

Gnomad NFE exome AF: 0.0568

Gnomad OTH exome AF: 0.0800

GnomAD4 exome AF: 0.0558 AC: 81351 AN: 1457196 Hom.: 2671 Cov.: 33 AF XY: 0.0564 AC XY: 40888 AN XY: 725192

Gnomad4 AFR exome AF: 0.0596

Gnomad4 AMR exome AF: 0.0497

Gnomad4 ASJ exome AF: 0.0949

Gnomad4 EAS exome AF: 0.125

Gnomad4 SAS exome AF: 0.0549

Gnomad4 FIN exome AF: 0.120

Gnomad4 NFE exome AF: 0.0489

Gnomad4 OTH exome AF: 0.0637

GnomAD4 genome AF: 0.0665 AC: 10127 AN: 152270 Hom.: 374 Cov.: 32 AF XY: 0.0705 AC XY: 5246 AN XY: 74438

Gnomad4 AFR AF: 0.0579

Gnomad4 AMR AF: 0.0655

Gnomad4 ASJ AF: 0.0956

Gnomad4 EAS AF: 0.140

Gnomad4 SAS AF: 0.0553

Gnomad4 FIN AF: 0.122

Gnomad4 NFE AF: 0.0574

Gnomad4 OTH AF: 0.0738

Alfa AF: 0.0461 Hom.: 49

Bravo AF: 0.0631

Asia WGS AF: 0.0980 AC: 339 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:5 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 07, 2013	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Mar 29, 2018	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 19, 2015	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. -

not provided Benign:1 Other:1

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
not provided, no classification provided	literature only	Leiden Muscular Dystrophy (RYR1)	-	- -

RYR1-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	1.0
DANN	Benign	0.55

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: rs2234709; hg19: chr19-38990676;