19-38527640-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.10687-7C>T variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.058 in 1,613,818 control chromosomes in the GnomAD database, including 4,971 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.12 (1793 hom., cov: 31)
  • Exomes 𝑓: 0.052 (3178 hom.)
• Consequence: RYR1 NM_000540.3 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.0002812
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts U:1 B:11 O:1
• Conservation: PhyloP100: 0.236

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]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.75).
• BP6: Variant 19-38527640-C-T is Benign according to our data. Variant chr19-38527640-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 93242.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-38527640-C-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.265 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RYR1	NM_000540.3	c.10687-7C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000359596.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RYR1	ENST00000359596.8	c.10687-7C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		5	NM_000540.3	A2
	ENST00000597015.1	n.371G>A		non_coding_transcript_exon_variant	2/3	4

Frequencies

GnomAD3 genomes AF: 0.118 AC: 17873 AN: 152086 Hom.: 1785 Cov.: 31

Gnomad AFR AF: 0.269

Gnomad AMI AF: 0.0208

Gnomad AMR AF: 0.0777

Gnomad ASJ AF: 0.0948

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.0362

Gnomad FIN AF: 0.118

Gnomad MID AF: 0.0796

Gnomad NFE AF: 0.0522

Gnomad OTH AF: 0.106

GnomAD3 exomes AF: 0.0675 AC: 16893 AN: 250186 Hom.: 1089 AF XY: 0.0627 AC XY: 8490 AN XY: 135380

Gnomad AFR exome AF: 0.280

Gnomad AMR exome AF: 0.0441

Gnomad ASJ exome AF: 0.0885

Gnomad EAS exome AF: 0.000163

Gnomad SAS exome AF: 0.0360

Gnomad FIN exome AF: 0.121

Gnomad NFE exome AF: 0.0517

Gnomad OTH exome AF: 0.0697

GnomAD4 exome AF: 0.0518 AC: 75674 AN: 1461614 Hom.: 3178 Cov.: 33 AF XY: 0.0511 AC XY: 37175 AN XY: 727088

Gnomad4 AFR exome AF: 0.275

Gnomad4 AMR exome AF: 0.0486

Gnomad4 ASJ exome AF: 0.0920

Gnomad4 EAS exome AF: 0.000202

Gnomad4 SAS exome AF: 0.0361

Gnomad4 FIN exome AF: 0.115

Gnomad4 NFE exome AF: 0.0433

Gnomad4 OTH exome AF: 0.0650

GnomAD4 genome AF: 0.118 AC: 17910 AN: 152204 Hom.: 1793 Cov.: 31 AF XY: 0.120 AC XY: 8934 AN XY: 74420

Gnomad4 AFR AF: 0.269

Gnomad4 AMR AF: 0.0775

Gnomad4 ASJ AF: 0.0948

Gnomad4 EAS AF: 0.000386

Gnomad4 SAS AF: 0.0363

Gnomad4 FIN AF: 0.118

Gnomad4 NFE AF: 0.0521

Gnomad4 OTH AF: 0.104

Alfa AF: 0.0644 Hom.: 841

Bravo AF: 0.123

Asia WGS AF: 0.0350 AC: 124 AN: 3478

EpiCase AF: 0.0575

EpiControl AF: 0.0551

ClinVar

Significance: Benign/Likely benign

Submissions summary: Uncertain:1 Benign:11 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

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	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Nov 24, 2014	10687-7C>T in intron 72 of RYR1: This variant is not expected to have clinical s ignificance because it has been identified in 26.2% (1155/4406) of African Ameri can chromosomes from a broad population by the NHLBI Exome Sequencing Project (h ttp://evs.gs.washington.edu/EVS; dbSNP rs2960354). -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Apr 02, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 05, 2013	- -
Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Aug 15, 2013	- -

not provided Uncertain:1 Other:1

not provided, no classification provided	literature only	Leiden Muscular Dystrophy (RYR1)	-	- -
Uncertain significance, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	Allele frequency is common in at least one population database (frequency: 27.994% in gnomAD_Exomes) based on the frequency threshold of 2.223% for this gene. Variant was observed in a homozygous state in population databases more than expected for disease. -

Malignant hyperthermia, susceptibility to, 1 Benign:2

Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Mar 05, 2018	- -
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

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. -

RYR1-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

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

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	-0.75
Cadd	Benign	12
Dann	Benign	0.58

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00028
dbscSNV1_RF	Benign	0.026
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: rs2960354; hg19: chr19-39018280;