rs754890674

Positions:

chr20-428578-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_031229.4(RBCK1):c.1297G>C(p.Glu433Gln) variant causes a missense change. The variant allele was found at a frequency of 0.00000621 in 1,611,124 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000055 ( 0 hom. )

Consequence

RBCK1
NM_031229.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 3.79

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 links:

TBC1D20 (HGNC:16133): (TBC1 domain family member 20) This gene encodes a protein that belongs to a family of GTPase activator proteins of Rab-like small GTPases. The encoded protein and its cognate GTPase, Rab1, bind the nonstructural protein 5A (NS5A) of the hepatitis C virus (HCV) to mediate viral replication. Depletion of this protein inhibits replication of the virus and HCV infection. Mutations in this gene are associated with Warburg micro syndrome 4. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Mar 2014]

TBC1D20 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.13051575).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RBCK1	NM_031229.4 linkuse as main transcript	c.1297G>C	p.Glu433Gln	missense_variant	10/12	ENST00000356286.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RBCK1	ENST00000356286.10 linkuse as main transcript	c.1297G>C	p.Glu433Gln	missense_variant	10/12	1	NM_031229.4	P1	Q9BYM8-1

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152254

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000412

AC:

AN:

243006

Hom.:

AF XY:

0.00

AC XY:

AN XY:

131816

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000911

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000548

AC:

AN:

1458870

Hom.:

Cov.:

AF XY:

0.00000551

AC XY:

AN XY:

725390

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000630

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152254

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74384

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000712

Hom.:

Bravo

AF:

0.0000113

ExAC

AF:

0.00000825

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 18, 2021

The c.1297G>C (p.E433Q) alteration is located in exon 10 (coding exon 10) of the RBCK1 gene. This alteration results from a G to C substitution at nucleotide position 1297, causing the glutamic acid (E) at amino acid position 433 to be replaced by a glutamine (Q). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Polyglucosan body myopathy type 1

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

May 11, 2022

This sequence change replaces glutamic acid, which is acidic and polar, with glutamine, which is neutral and polar, at codon 433 of the RBCK1 protein (p.Glu433Gln). This variant is present in population databases (rs754890674, gnomAD 0.002%). This variant has not been reported in the literature in individuals affected with RBCK1-related conditions. ClinVar contains an entry for this variant (Variation ID: 578757). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.094

BayesDel_addAF

Benign

-0.15

BayesDel_noAF

Benign

-0.46

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.14

T;.;.;.

Eigen

Benign

-0.043

Eigen_PC

Benign

0.16

FATHMM_MKL

Uncertain

0.80

LIST_S2

Uncertain

0.90

D;D;D;.

M_CAP

Benign

0.0066

MetaRNN

Benign

0.13

T;T;T;T

MetaSVM

Benign

-0.98

MutationAssessor

Benign

0.10

N;.;.;.

MutationTaster

Benign

0.94

D;D;D

PrimateAI

Benign

0.43

PROVEAN

Benign

-0.64

N;.;N;N

REVEL

Benign

0.057

Sift

Benign

0.33

T;.;T;T

Sift4G

Benign

0.45

T;.;T;T

Polyphen

0.28

B;B;B;B

Vest4

0.27

MutPred

0.32

Gain of MoRF binding (P = 0.023);.;.;.;

MVP

0.52

MPC

0.62

ClinPred

0.33

GERP RS

4.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.15

gMVP

0.56

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over