NM_000540.3:c.12861_12869delCACGGCGGC

Variant names:

• chr19-38565185-GCACGGCGGC-G
• rs398123469
• NM_000540.3:c.12861_12869delCACGGCGGC

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP3 BP6 BS1

The NM_000540.3(RYR1):​c.12861_12869delCACGGCGGC​(p.Thr4288_Ala4290del) variant causes a disruptive inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00062 in 1,117,954 control chromosomes in the GnomAD database, including 2 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0027 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00030 (1 hom.)
• Consequence: RYR1 NM_000540.3 disruptive_inframe_deletion
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:2
• Conservation: PhyloP100: 1.70
• Publications: 4 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), PanelApp Australia, Genomics England PanelApp, Ambry Genetics, ClinGen
• RYR1-related myopathy

  Inheritance: AD, AR Classification: DEFINITIVE, STRONG Submitted by: ClinGen, PanelApp Australia
• congenital multicore myopathy with external ophthalmoplegia

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Genomics England PanelApp
• central core myopathy

  Inheritance: AD, AR Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), 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: Likely_benign. The variant received -6 ACMG points.

• BP3: Nonframeshift variant in repetitive region in NM_000540.3
• BP6: Variant 19-38565185-GCACGGCGGC-G is Benign according to our data. Variant chr19-38565185-GCACGGCGGC-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 285661.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00271 (400/147618) while in subpopulation AFR AF = 0.00909 (373/41046). AF 95% confidence interval is 0.00833. There are 1 homozygotes in GnomAd4. There are 200 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000540.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RYR1	NM_000540.3	MANE Select	c.12861_12869delCACGGCGGC	p.Thr4288_Ala4290del	disruptive_inframe_deletion	Exon 91 of 106	NP_000531.2	P21817-1
	RYR1	NM_001042723.2		c.12846_12854delCACGGCGGC	p.Thr4283_Ala4285del	disruptive_inframe_deletion	Exon 90 of 105	NP_001036188.1	P21817-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RYR1	ENST00000359596.8	TSL:5 MANE Select	c.12861_12869delCACGGCGGC	p.Thr4288_Ala4290del	disruptive_inframe_deletion	Exon 91 of 106	ENSP00000352608.2	P21817-1
	RYR1	ENST00000355481.8	TSL:1	c.12846_12854delCACGGCGGC	p.Thr4283_Ala4285del	disruptive_inframe_deletion	Exon 90 of 105	ENSP00000347667.3	P21817-2
	RYR1	ENST00000594335.6	TSL:1	n.*3571_*3579delCACGGCGGC		non_coding_transcript_exon	Exon 88 of 103	ENSP00000470927.2	M0R014

Frequencies

GnomAD3 genomes AF: 0.00270 AC: 398 AN: 147512 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00906

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000809

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000829

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000106

Gnomad OTH AF: 0.00197

GnomAD2 exomes AF: 0.000391 AC: 1 AN: 2558 AF XY: 0.000567

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000302 AC: 293 AN: 970336 Hom.: 1 AF XY: 0.000302 AC XY: 138 AN XY: 456652

African (AFR) AF: 0.00929 AC: 176 AN: 18946

American (AMR) AF: 0.000403 AC: 2 AN: 4962

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 9642

East Asian (EAS) AF: 0.00 AC: 0 AN: 16164

South Asian (SAS) AF: 0.000902 AC: 17 AN: 18856

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 14294

Middle Eastern (MID) AF: 0.00347 AC: 8 AN: 2308

European-Non Finnish (NFE) AF: 0.0000718 AC: 61 AN: 849438

Other (OTH) AF: 0.000812 AC: 29 AN: 35726

GnomAD4 genome AF: 0.00271 AC: 400 AN: 147618 Hom.: 1 Cov.: 32 AF XY: 0.00278 AC XY: 200 AN XY: 71954

African (AFR) AF: 0.00909 AC: 373 AN: 41046

American (AMR) AF: 0.000808 AC: 12 AN: 14852

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3410

East Asian (EAS) AF: 0.00 AC: 0 AN: 5112

South Asian (SAS) AF: 0.000830 AC: 4 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 8786

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 290

European-Non Finnish (NFE) AF: 0.000106 AC: 7 AN: 66338

Other (OTH) AF: 0.00195 AC: 4 AN: 2054

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	1	not provided (2)
-	1	-	King Denborough syndrome;C1850674:Congenital multicore myopathy with external ophthalmoplegia;C2930980:Malignant hyperthermia, susceptibility to, 1;C5830701:Central core myopathy (1)
-	-	1	RYR1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.7
Mutation Taster		=126/74	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs398123469; hg19: chr19-39055825;