rs750824483

Variant names:

• chr19-38575899-TTCTC-T
• rs750824483
• NM_000540.3:c.14130-8_14130-5delCTCT

Your query was ambiguous. Multiple possible variants found:

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

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP6_Very_Strong

The ENST00000359596.8(RYR1):​c.14130-19_14130-16delTCTC variant causes a 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 ENST00000359596.8 intron
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 1.47
• Publications: 0 publications found

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]

RYR1 Gene-Disease associations (from GenCC):

• malignant hyperthermia, susceptibility to, 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, Genomics England PanelApp, Ambry Genetics
• congenital multicore myopathy with external ophthalmoplegia

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Genomics England PanelApp
• RYR1-related myopathy

  Inheritance: AR, AD Classification: DEFINITIVE Submitted by: ClinGen
• central core myopathy

  Inheritance: AD, AR Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, Genomics England PanelApp
• King-Denborough syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• malignant hyperthermia of anesthesia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• autosomal recessive centronuclear myopathy

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• benign Samaritan congenital myopathy

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• congenital myopathy with myasthenic-like onset

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• lethal multiple pterygium syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 256440.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000359596.8. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RYR1	NM_000540.3	MANE Select	c.14130-8_14130-5delCTCT		splice_region intron	N/A	NP_000531.2
	RYR1	NM_001042723.2		c.14115-8_14115-5delCTCT		splice_region intron	N/A	NP_001036188.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RYR1	ENST00000359596.8	TSL:5 MANE Select	c.14130-19_14130-16delTCTC		intron	N/A	ENSP00000352608.2
	RYR1	ENST00000355481.8	TSL:1	c.14115-19_14115-16delTCTC		intron	N/A	ENSP00000347667.3
	RYR1	ENST00000594335.6	TSL:1	n.*4840-19_*4840-16delTCTC		intron	N/A	ENSP00000470927.2

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

GnomAD2 exomes AF: 0.000152 AC: 35 AN: 230102 AF XY: 0.000129

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 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

African (AFR) AF: 0.0000608 AC: 2 AN: 32902

American (AMR) AF: 0.00 AC: 0 AN: 44286

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25740

East Asian (EAS) AF: 0.000128 AC: 5 AN: 39090

South Asian (SAS) AF: 0.00 AC: 0 AN: 85230

European-Finnish (FIN) AF: 0.000607 AC: 32 AN: 52752

Middle Eastern (MID) AF: 0.000351 AC: 2 AN: 5698

European-Non Finnish (NFE) AF: 0.0000797 AC: 87 AN: 1091580

Other (OTH) AF: 0.0000674 AC: 4 AN: 59306

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

African (AFR) AF: 0.0000482 AC: 2 AN: 41456

American (AMR) AF: 0.0000657 AC: 1 AN: 15228

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3462

East Asian (EAS) AF: 0.000775 AC: 4 AN: 5158

South Asian (SAS) AF: 0.00 AC: 0 AN: 4802

European-Finnish (FIN) AF: 0.000192 AC: 2 AN: 10440

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000354 AC: 24 AN: 67792

Other (OTH) AF: 0.000476 AC: 1 AN: 2100

Alfa AF: 0.000618 Hom.: 0

Bravo AF: 0.0000718

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)
-	-	1	not specified (1)
-	-	1	RYR1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.5
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs750824483; hg19: chr19-39066539;