rs750824483

Positions:

• chr19-38575899-TTCTC-T
• chr19-38575899-TTCTC-TTC
• chr19-38575899-TTCTC-TTCTCTC
• chr19-38575899-TTCTC-TTCTCTCTC

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP6_Very_Strong

The NM_000540.3(RYR1):​c.14130-8_14130-5del variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000105 in 1,588,226 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00022 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000092 (0 hom.)
• Consequence: RYR1 NM_000540.3 splice_polypyrimidine_tract, intron
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 1.47

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 -8 ACMG points.

• BP6: Variant 19-38575899-TTCTC-T is Benign according to our data. Variant chr19-38575899-TTCTC-T is described in ClinVar as [Likely_benign]. Clinvar id is 256440.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RYR1	NM_000540.3	c.14130-8_14130-5del		splice_polypyrimidine_tract_variant, intron_variant		ENST00000359596.8	NP_000531.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RYR1	ENST00000359596.8	c.14130-8_14130-5del		splice_polypyrimidine_tract_variant, intron_variant		5	NM_000540.3	ENSP00000352608	A2

Frequencies

GnomAD3 genomes AF: 0.000224 AC: 34 AN: 151526 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000484

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000658

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000774

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000192

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000354

Gnomad OTH AF: 0.000481

GnomAD3 exomes AF: 0.000152 AC: 35 AN: 230102 Hom.: 0 AF XY: 0.000129 AC XY: 16 AN XY: 124236

Gnomad AFR exome AF: 0.0000651

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000650

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000646

Gnomad NFE exome AF: 0.0000861

Gnomad OTH exome AF: 0.000180

GnomAD4 exome AF: 0.0000919 AC: 132 AN: 1436584 Hom.: 0 AF XY: 0.0000881 AC XY: 63 AN XY: 715026

Gnomad4 AFR exome AF: 0.0000608

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000128

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.000607

Gnomad4 NFE exome AF: 0.0000797

Gnomad4 OTH exome AF: 0.0000674

GnomAD4 genome AF: 0.000224 AC: 34 AN: 151642 Hom.: 0 Cov.: 32 AF XY: 0.000175 AC XY: 13 AN XY: 74104

Gnomad4 AFR AF: 0.0000482

Gnomad4 AMR AF: 0.0000657

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000775

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000192

Gnomad4 NFE AF: 0.000354

Gnomad4 OTH AF: 0.000476

Alfa AF: 0.000618 Hom.: 0

Bravo AF: 0.0000718

ClinVar

Significance: Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

RYR1-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 17, 2023

- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Sep 01, 2022

RYR1: BP4, BS1 -

Computational scores

Source: dbNSFP v4.3

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: rs750824483; hg19: chr19-39066539;