NM_000540.3:c.12861_12869dupCACGGCGGC

Variant names:

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP3BP6BS1BS2

The NM_000540.3(RYR1):c.12861_12869dupCACGGCGGC(p.Ala4290_Ala4291insThrAlaAla) variant causes a disruptive inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00156 in 1,117,934 control chromosomes in the GnomAD database, including 25 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0075 ( 15 hom., cov: 32)

Exomes 𝑓: 0.00065 ( 10 hom. )

Consequence

RYR1
NM_000540.3 disruptive_inframe_insertion

Scores

Not classified

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:6

Conservation

PhyloP100: 0.273

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), 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

RYR1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -10 ACMG points.

BP3

Nonframeshift variant in repetitive region in NM_000540.3

BP6

Variant 19-38565185-G-GCACGGCGGC is Benign according to our data. Variant chr19-38565185-G-GCACGGCGGC is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 93248.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00749 (1106/147610) while in subpopulation AFR AF = 0.0255 (1045/41038). AF 95% confidence interval is 0.0242. There are 15 homozygotes in GnomAd4. There are 522 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 15 AR,AD gene

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_12869dupCACGGCGGC	p.Ala4290_Ala4291insThrAlaAla	disruptive_inframe_insertion	Exon 91 of 106	NP_000531.2	P21817-1
	RYR1	NM_001042723.2		c.12846_12854dupCACGGCGGC	p.Ala4285_Ala4286insThrAlaAla	disruptive_inframe_insertion	Exon 90 of 105	NP_001036188.1	P21817-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
RYR1	ENST00000359596.8	TSL:5 MANE Select	c.12861_12869dupCACGGCGGC	p.Ala4290_Ala4291insThrAlaAla	disruptive_inframe_insertion	Exon 91 of 106	ENSP00000352608.2	P21817-1
RYR1	ENST00000355481.8	TSL:1	c.12846_12854dupCACGGCGGC	p.Ala4285_Ala4286insThrAlaAla	disruptive_inframe_insertion	Exon 90 of 105	ENSP00000347667.3	P21817-2
RYR1	ENST00000594335.6	TSL:1	n.3571_3579dupCACGGCGGC		non_coding_transcript_exon	Exon 88 of 103	ENSP00000470927.2	M0R014

Frequencies

GnomAD3 genomes

AF:

0.00745

AC:

1099

AN:

147504

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0254

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00297

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000390

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00321

Gnomad NFE

AF:

0.0000603

Gnomad OTH

AF:

0.00443

GnomAD4 exome

AF:

0.000654

AC:

635

AN:

970324

Hom.:

Cov.:

AF XY:

0.000644

AC XY:

294

AN XY:

456650

show subpopulations

African (AFR)

AF:

0.0284

AC:

538

AN:

18936

American (AMR)

AF:

0.00

AC:

AN:

4962

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

9642

East Asian (EAS)

AF:

0.0000619

AC:

AN:

16164

South Asian (SAS)

AF:

0.000212

AC:

AN:

18856

European-Finnish (FIN)

AF:

0.00

AC:

AN:

14294

Middle Eastern (MID)

AF:

0.00433

AC:

AN:

2308

European-Non Finnish (NFE)

AF:

0.0000188

AC:

AN:

849438

Other (OTH)

AF:

0.00185

AC:

AN:

35724

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.445

Heterozygous variant carriers

126

157

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

120

150

<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:

0.00749

AC:

1106

AN:

147610

Hom.:

Cov.:

AF XY:

0.00726

AC XY:

522

AN XY:

71946

show subpopulations

African (AFR)

AF:

0.0255

AC:

1045

AN:

41038

American (AMR)

AF:

0.00296

AC:

AN:

14852

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3410

East Asian (EAS)

AF:

0.000391

AC:

AN:

5112

South Asian (SAS)

AF:

0.000207

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.00

AC:

AN:

8786

Middle Eastern (MID)

AF:

0.00345

AC:

AN:

290

European-Non Finnish (NFE)

AF:

0.0000603

AC:

AN:

66338

Other (OTH)

AF:

0.00438

AC:

AN:

2054

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

100

150

200

250

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome 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

Alfa

AF:

0.00

Hom.:

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

not specified (2)

RYR1-related disorder (2)

Inborn genetic diseases (1)

Limb-girdle muscular dystrophy (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

0.27

Mutation Taster

=73/27

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over