rs2234709

Variant names:

• chr19-38500036-C-A
• rs2234709
• NM_000540.3:c.7323+20C>A

Your query was ambiguous. Multiple possible variants found:

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

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 4 publications found

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]

RYR1 Gene-Disease associations (from GenCC):

• malignant hyperthermia, susceptibility to, 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, Genomics England PanelApp, Ambry Genetics
• congenital multicore myopathy with external ophthalmoplegia

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Genomics England PanelApp
• RYR1-related myopathy

  Inheritance: AR, AD Classification: DEFINITIVE Submitted by: ClinGen
• central core myopathy

  Inheritance: AD, AR Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, Genomics England PanelApp
• King-Denborough syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• malignant hyperthermia of anesthesia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• autosomal recessive centronuclear myopathy

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• benign Samaritan congenital myopathy

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• congenital myopathy with myasthenic-like onset

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• lethal multiple pterygium syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 93286.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 rank	MANE	Protein	UniProt
RYR1	NM_000540.3	c.7323+20C>A		intron_variant	Intron 45 of 105	ENST00000359596.8	NP_000531.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RYR1	ENST00000359596.8	c.7323+20C>A		intron_variant	Intron 45 of 105	5	NM_000540.3	ENSP00000352608.2

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

GnomAD2 exomes AF: 0.0693 AC: 17315 AN: 249882 AF XY: 0.0688

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 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

African (AFR) AF: 0.0596 AC: 1989 AN: 33382

American (AMR) AF: 0.0497 AC: 2220 AN: 44696

Ashkenazi Jewish (ASJ) AF: 0.0949 AC: 2477 AN: 26104

East Asian (EAS) AF: 0.125 AC: 4971 AN: 39672

South Asian (SAS) AF: 0.0549 AC: 4726 AN: 86158

European-Finnish (FIN) AF: 0.120 AC: 6374 AN: 53088

Middle Eastern (MID) AF: 0.0954 AC: 548 AN: 5742

European-Non Finnish (NFE) AF: 0.0489 AC: 54210 AN: 1108116

Other (OTH) AF: 0.0637 AC: 3836 AN: 60238

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

African (AFR) AF: 0.0579 AC: 2408 AN: 41562

American (AMR) AF: 0.0655 AC: 1003 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.0956 AC: 332 AN: 3472

East Asian (EAS) AF: 0.140 AC: 722 AN: 5162

South Asian (SAS) AF: 0.0553 AC: 267 AN: 4830

European-Finnish (FIN) AF: 0.122 AC: 1292 AN: 10606

Middle Eastern (MID) AF: 0.0748 AC: 22 AN: 294

European-Non Finnish (NFE) AF: 0.0574 AC: 3906 AN: 68014

Other (OTH) AF: 0.0738 AC: 156 AN: 2114

Alfa AF: 0.0461 Hom.: 50

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

May 07, 2013

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 29, 2018

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 19, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

-

RYR1 database

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

RYR1-related disorder Benign:1

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	1.0
DANN	Benign	0.55
PhyloP100		-0.098
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2234709; hg19: chr19-38990676;