NM_000540.3:c.12861_12869delCACGGCGGC

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP3BP6BS1

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

Scores

Not classified

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:2

Conservation

PhyloP100: 1.70

Publications

4 publications found

Variant links:

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

RYR1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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 CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 285661. Variant chr19-38565185-GCACGGCGGC-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 285661. Variant chr19-38565185-GCACGGCGGC-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 285661. Variant chr19-38565185-GCACGGCGGC-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 285661. Variant chr19-38565185-GCACGGCGGC-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 285661. Variant chr19-38565185-GCACGGCGGC-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 285661. Variant chr19-38565185-GCACGGCGGC-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 285661. Variant chr19-38565185-GCACGGCGGC-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RYR1	NM_000540.3 link	c.12861_12869delCACGGCGGC	p.Thr4288_Ala4290del	disruptive_inframe_deletion	Exon 91 of 106	ENST00000359596.8	NP_000531.2	P21817-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RYR1	ENST00000359596.8 link	c.12861_12869delCACGGCGGC	p.Thr4288_Ala4290del	disruptive_inframe_deletion	Exon 91 of 106	5	NM_000540.3	ENSP00000352608.2		P21817-1

Frequencies

GnomAD3 genomes

AF:

0.00270

AC:

398

AN:

147512

Hom.:

Cov.:

show subpopulations

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:

AN:

2558

AF XY:

0.000567

show subpopulations

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.:

AF XY:

0.000302

AC XY:

138

AN XY:

456652

show subpopulations

African (AFR)

AF:

0.00929

AC:

176

AN:

18946

American (AMR)

AF:

0.000403

AC:

AN:

4962

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

9642

East Asian (EAS)

AF:

0.00

AC:

AN:

16164

South Asian (SAS)

AF:

0.000902

AC:

AN:

18856

European-Finnish (FIN)

AF:

0.00

AC:

AN:

14294

Middle Eastern (MID)

AF:

0.00347

AC:

AN:

2308

European-Non Finnish (NFE)

AF:

0.0000718

AC:

AN:

849438

Other (OTH)

AF:

0.000812

AC:

AN:

35726

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.526

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00271

AC:

400

AN:

147618

Hom.:

Cov.:

AF XY:

0.00278

AC XY:

200

AN XY:

71954

show subpopulations

African (AFR)

AF:

0.00909

AC:

373

AN:

41046

American (AMR)

AF:

0.000808

AC:

AN:

14852

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3410

East Asian (EAS)

AF:

0.00

AC:

AN:

5112

South Asian (SAS)

AF:

0.000830

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.00

AC:

AN:

8786

Middle Eastern (MID)

AF:

0.00

AC:

AN:

290

European-Non Finnish (NFE)

AF:

0.000106

AC:

AN:

66338

Other (OTH)

AF:

0.00195

AC:

AN:

2054

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.487

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:1

Jan 11, 2016

Eurofins Ntd Llc (ga)

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

RYR1: PM4, BS2 -

King Denborough syndrome;C1850674:Congenital multicore myopathy with external ophthalmoplegia;C2930980:Malignant hyperthermia, susceptibility to, 1;C5830701:Central core myopathy

Uncertain:1

Dec 08, 2021

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:research

- -

RYR1-related disorder

Benign:1

Aug 06, 2023

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

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). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

1.7

Mutation Taster

=126/74

polymorphism

(source)

Splicing

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over