rs559371263

Positions:

• chr19-38489293-TGAG-T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BS1 BS2

The NM_000540.3(RYR1):​c.5671_5673del​(p.Glu1891del) variant causes a inframe deletion change. The variant allele was found at a frequency of 0.000482 in 1,601,590 control chromosomes in the GnomAD database, including 5 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00035 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00050 (5 hom.)
• Consequence: RYR1 NM_000540.3 inframe_deletion
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 5.29

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 -16 ACMG points.

• BP6: Variant 19-38489293-TGAG-T is Benign according to our data. Variant chr19-38489293-TGAG-T is described in ClinVar as [Likely_benign]. Clinvar id is 196940.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. gnomad4_exome allele frequency = 0.000495 (719/1451678) while in subpopulation SAS AF= 0.0037 (318/86032). AF 95% confidence interval is 0.00336. There are 5 homozygotes in gnomad4_exome. There are 416 alleles in male gnomad4_exome subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 5 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RYR1	NM_000540.3	c.5671_5673del	p.Glu1891del	inframe_deletion	35/106	ENST00000359596.8	NP_000531.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RYR1	ENST00000359596.8	c.5671_5673del	p.Glu1891del	inframe_deletion	35/106	5	NM_000540.3	ENSP00000352608	A2
RYR1	ENST00000355481.8	c.5671_5673del	p.Glu1891del	inframe_deletion	35/105	1		ENSP00000347667	P4
RYR1	ENST00000599547.6	c.5671_5673del	p.Glu1891del	inframe_deletion, NMD_transcript_variant	35/80	2		ENSP00000471601

Frequencies

GnomAD3 genomes AF: 0.000354 AC: 53 AN: 149794 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000493

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000266

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000392

Gnomad SAS AF: 0.00298

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00325

Gnomad NFE AF: 0.000163

Gnomad OTH AF: 0.000486

GnomAD3 exomes AF: 0.000749 AC: 185 AN: 247138 Hom.: 4 AF XY: 0.000889 AC XY: 119 AN XY: 133834

Gnomad AFR exome AF: 0.000371

Gnomad AMR exome AF: 0.000233

Gnomad ASJ exome AF: 0.0000997

Gnomad EAS exome AF: 0.000164

Gnomad SAS exome AF: 0.00430

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000308

Gnomad OTH exome AF: 0.000329

GnomAD4 exome AF: 0.000495 AC: 719 AN: 1451678 Hom.: 5 AF XY: 0.000576 AC XY: 416 AN XY: 722826

Gnomad4 AFR exome AF: 0.000210

Gnomad4 AMR exome AF: 0.000179

Gnomad4 ASJ exome AF: 0.0000384

Gnomad4 EAS exome AF: 0.0000757

Gnomad4 SAS exome AF: 0.00370

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000311

Gnomad4 OTH exome AF: 0.000649

GnomAD4 genome AF: 0.000354 AC: 53 AN: 149912 Hom.: 0 Cov.: 32 AF XY: 0.000397 AC XY: 29 AN XY: 73094

Gnomad4 AFR AF: 0.000492

Gnomad4 AMR AF: 0.000266

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000393

Gnomad4 SAS AF: 0.00298

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000163

Gnomad4 OTH AF: 0.000481

Alfa AF: 0.000182 Hom.: 0

Bravo AF: 0.000264

Asia WGS AF: 0.00318 AC: 11 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

RYR1-related disorder Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Likely benign, no assertion criteria provided	clinical testing	PreventionGenetics, part of Exact Sciences	Jun 24, 2019	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 07, 2022	See Variant Classification Assertion Criteria. -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2024	RYR1: BS2 -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Feb 18, 2015

- -

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: rs559371263; hg19: chr19-38979933;