Genetic Variant RBCK1:p.Glu243* (chr20-419702-G-T) – ACMG Classification: Pathogenic (11 pts)

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PVS1PM2PP5

The NM_031229.4(RBCK1):c.727G>T(p.Glu243*) variant causes a stop gained change. The variant allele was found at a frequency of 0.000000705 in 1,417,884 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 7.1e-7 ( 0 hom. )

Consequence

RBCK1
NM_031229.4 stop_gained

Scores

Clinical Significance

Pathogenic no assertion criteria provided P:1

Conservation

PhyloP100: 5.82

Publications

4 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:

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ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 11 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 20-419702-G-T is Pathogenic according to our data. Variant chr20-419702-G-T is described in ClinVar as Pathogenic. ClinVar VariationId is 140627.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RBCK1	NM_031229.4 link	c.727G>T	p.Glu243*	stop_gained	Exon 6 of 12	ENST00000356286.10	NP_112506.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RBCK1	ENST00000356286.10 link	c.727G>T	p.Glu243*	stop_gained	Exon 6 of 12	1	NM_031229.4	ENSP00000348632.6

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.05e-7

AC:

AN:

1417884

Hom.:

Cov.:

AF XY:

0.00000142

AC XY:

AN XY:

702256

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32648

American (AMR)

AF:

0.00

AC:

AN:

39602

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25396

East Asian (EAS)

AF:

0.0000267

AC:

AN:

37476

South Asian (SAS)

AF:

0.00

AC:

AN:

81472

European-Finnish (FIN)

AF:

0.00

AC:

AN:

43188

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5694

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1093508

Other (OTH)

AF:

0.00

AC:

AN:

58900

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

Polyglucosan body myopathy type 1

Pathogenic:1

Dec 01, 2013

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.59

BayesDel_noAF

Pathogenic

0.50

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

Eigen

Pathogenic

0.82

Eigen_PC

Uncertain

0.62

FATHMM_MKL

Uncertain

0.81

PhyloP100

5.8

Vest4

0.91

GERP RS

2.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=4/196

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over