19-38433765-G-C

Position:

• chr19-38433765-G-C

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BP4_Strong

The NM_000540.3(RYR1):​c.-65G>C variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.019 (0 hom., cov: 0)
  • Exomes 𝑓: 0.12 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: RYR1 NM_000540.3 5_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:3
• Conservation: PhyloP100: 0.515

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 Likely_benign. Variant got -4 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RYR1	NM_000540.3	c.-65G>C		5_prime_UTR_variant	1/106	ENST00000359596.8	NP_000531.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RYR1	ENST00000359596.8	c.-65G>C		5_prime_UTR_variant	1/106	5	NM_000540.3	ENSP00000352608	A2
RYR1	ENST00000355481.8	c.-65G>C		5_prime_UTR_variant	1/105	1		ENSP00000347667	P4

Frequencies

GnomAD3 genomes AF: 0.00 AC: 217 AN: 11190 Hom.: 0 Cov.: 0 FAILED QC

Gnomad AFR AF: 0.0149

Gnomad AMI AF: 0.0179

Gnomad AMR AF: 0.0180

Gnomad ASJ AF: 0.0179

Gnomad EAS AF: 0.0283

Gnomad SAS AF: 0.0479

Gnomad FIN AF: 0.0370

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0165

Gnomad OTH AF: 0.0127

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.124 AC: 21518 AN: 174076 Hom.: 0 Cov.: 0 AF XY: 0.115 AC XY: 11405 AN XY: 98908

Gnomad4 AFR exome AF: 0.139

Gnomad4 AMR exome AF: 0.0568

Gnomad4 ASJ exome AF: 0.135

Gnomad4 EAS exome AF: 0.190

Gnomad4 SAS exome AF: 0.0388

Gnomad4 FIN exome AF: 0.0759

Gnomad4 NFE exome AF: 0.146

Gnomad4 OTH exome AF: 0.175

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.0192 AC: 215 AN: 11222 Hom.: 0 Cov.: 0 AF XY: 0.0176 AC XY: 104 AN XY: 5908

Gnomad4 AFR AF: 0.0143

Gnomad4 AMR AF: 0.0172

Gnomad4 ASJ AF: 0.0179

Gnomad4 EAS AF: 0.0286

Gnomad4 SAS AF: 0.0477

Gnomad4 FIN AF: 0.0370

Gnomad4 NFE AF: 0.0165

Gnomad4 OTH AF: 0.0122

Alfa AF: 0.0139 Hom.: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, single submitter

Submissions by phenotype

Congenital multicore myopathy with external ophthalmoplegia Uncertain:1

Uncertain significance, 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Central core myopathy Uncertain:1

Uncertain significance, 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Malignant hyperthermia, susceptibility to, 1 Uncertain:1

Uncertain significance, 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	4.0
DANN	Benign	0.48

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1204515719; hg19: chr19-38924405;