chr19-38433757-G-GC

Variant names:

• chr19-38433757-G-GC
• rs886054376
• NM_000540.3:c.-70dupC

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.

The NM_000540.3(RYR1):​c.-70dupC variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000195 in 179,356 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 26)
  • Exomes 𝑓: 0.00020 (0 hom.)
• Consequence: RYR1 NM_000540.3 5_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:4
• Conservation: PhyloP100: -0.211

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

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RYR1	NM_000540.3	c.-70dupC		5_prime_UTR_variant	Exon 1 of 106	ENST00000359596.8	NP_000531.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RYR1	ENST00000359596	c.-70dupC		5_prime_UTR_variant	Exon 1 of 106	5	NM_000540.3	ENSP00000352608.2
RYR1	ENST00000355481	c.-70dupC		5_prime_UTR_variant	Exon 1 of 105	1		ENSP00000347667.3
RYR1	ENST00000599547.6	n.-73_-72insC		upstream_gene_variant		2		ENSP00000471601.2

Frequencies

GnomAD3 genomes Cov.: 26

GnomAD4 exome AF: 0.000195 AC: 35 AN: 179356 Hom.: 0 Cov.: 0 AF XY: 0.000210 AC XY: 21 AN XY: 100136

Gnomad4 AFR exome AF: 0.00 AC: 0 AN: 6368

Gnomad4 AMR exome AF: 0.00 AC: 0 AN: 13290

Gnomad4 ASJ exome AF: 0.00 AC: 0 AN: 6330

Gnomad4 EAS exome AF: 0.00 AC: 0 AN: 8168

Gnomad4 SAS exome AF: 0.000413 AC: 10 AN: 24226

Gnomad4 FIN exome AF: 0.0000649 AC: 1 AN: 15404

Gnomad4 NFE exome AF: 0.000237 AC: 23 AN: 97012

Gnomad4 Remaining exome AF: 0.000125 AC: 1 AN: 8020

⚠️ The allele balance in gnomAD4 Exomes is highly skewed (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 26

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, single submitter

Submissions by phenotype

Malignant hyperthermia of anesthesia Uncertain:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Multiminicore myopathy Uncertain:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Central core myopathy Uncertain:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs886054376; hg19: chr19-38924397;