rs727503764

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_031229.4(RBCK1):c.896_899delAGTG(p.Glu299ValfsTer46) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000148 in 1,415,042 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: not found (cov: 27)

Exomes 𝑓: 0.000015 ( 0 hom. )

Consequence

RBCK1
NM_031229.4 frameshift

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:4

Conservation

PhyloP100: 9.69

Publications

7 publications found

Variant links:

Genes affected

RBCK1 (HGNC:15864): (RANBP2-type and C3HC4-type zinc finger containing 1) Enables several functions, including identical protein binding activity; protein sequestering activity; and ubiquitin binding activity. Involved in several processes, including T cell receptor signaling pathway; cellular protein metabolic process; and regulation of DNA-binding transcription factor activity. Part of LUBAC complex. Implicated in glycogen storage disease. [provided by Alliance of Genome Resources, Apr 2022]

RBCK1 Gene-Disease associations (from GenCC):

polyglucosan body myopathy 1 with or without immunodeficiency
Inheritance: AR Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, PanelApp Australia
autoinflammatory syndrome with pyogenic bacterial infection and amylopectinosis
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
polyglucosan body myopathy type 1
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

RBCK1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 18 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 20-421006-CGTGA-C is Pathogenic according to our data. Variant chr20-421006-CGTGA-C is described in ClinVar as Pathogenic. ClinVar VariationId is 140625.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_031229.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
RBCK1	NM_031229.4	MANE Select	c.896_899delAGTG	p.Glu299ValfsTer46	frameshift	Exon 7 of 12	NP_112506.2
RBCK1	NM_001410770.1		c.947_950delAGTG	p.Glu316ValfsTer46	frameshift	Exon 7 of 12	NP_001397699.1
RBCK1	NM_006462.6		c.770_773delAGTG	p.Glu257ValfsTer46	frameshift	Exon 6 of 11	NP_006453.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
RBCK1	ENST00000356286.10	TSL:1 MANE Select	c.896_899delAGTG	p.Glu299ValfsTer46	frameshift	Exon 7 of 12	ENSP00000348632.6
RBCK1	ENST00000353660.7	TSL:1	c.770_773delAGTG	p.Glu257ValfsTer46	frameshift	Exon 6 of 11	ENSP00000254960.5
RBCK1	ENST00000382181.2	TSL:1	n.631-1117_631-1114delAGTG		intron	N/A	ENSP00000371616.3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.0000114

AC:

AN:

175738

AF XY:

0.0000211

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000357

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000214

GnomAD4 exome

AF:

0.0000148

AC:

AN:

1415042

Hom.:

AF XY:

0.0000143

AC XY:

AN XY:

699810

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32350

American (AMR)

AF:

0.0000256

AC:

AN:

39088

Ashkenazi Jewish (ASJ)

AF:

0.0000396

AC:

AN:

25266

East Asian (EAS)

AF:

0.00

AC:

AN:

37096

South Asian (SAS)

AF:

0.0000372

AC:

AN:

80644

European-Finnish (FIN)

AF:

0.00

AC:

AN:

48164

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4868

European-Non Finnish (NFE)

AF:

0.0000138

AC:

AN:

1089040

Other (OTH)

AF:

0.0000171

AC:

AN:

58526

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.454

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Polyglucosan body myopathy type 1

Pathogenic:4

Jun 07, 2019

Institute of Human Genetics Munich, TUM University Hospital

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Dec 01, 2013

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

Feb 08, 2021

Institute of Human Genetics, Clinical Exome/Genome Diagnostics Group, University Hospital Bonn

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PVS1, PS4_moderate, PM2

Jul 30, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change creates a premature translational stop signal (p.Glu299Valfs*46) in the RBCK1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in RBCK1 are known to be pathogenic (PMID: 2379848, 23104095, 23889995). This variant is present in population databases (rs727503764, gnomAD 0.004%). This premature translational stop signal has been observed in individuals with clinical features of polyglucosan body myopathy with or without immunodeficiency (PMID: 23798481, 29260357, 31407473). ClinVar contains an entry for this variant (Variation ID: 140625). For these reasons, this variant has been classified as Pathogenic.

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

9.7

Mutation Taster

=3/197

disease causing (ClinVar)

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over