Genetic Variant NM_031229.4:c.436G>C (chr20-417906-G-C) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_031229.4(RBCK1):c.436G>C(p.Glu146Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,457,972 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E146K) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

RBCK1
NM_031229.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.13

Publications

0 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: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.071924865).

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.436G>C	p.Glu146Gln	missense	Exon 4 of 12	NP_112506.2
RBCK1	NM_001410770.1		c.487G>C	p.Glu163Gln	missense	Exon 4 of 12	NP_001397699.1
RBCK1	NM_006462.6		c.310G>C	p.Glu104Gln	missense	Exon 3 of 11	NP_006453.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
RBCK1	ENST00000356286.10	TSL:1 MANE Select	c.436G>C	p.Glu146Gln	missense	Exon 4 of 12	ENSP00000348632.6
RBCK1	ENST00000353660.7	TSL:1	c.310G>C	p.Glu104Gln	missense	Exon 3 of 11	ENSP00000254960.5
RBCK1	ENST00000382181.2	TSL:1	n.310G>C		non_coding_transcript_exon	Exon 3 of 10	ENSP00000371616.3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1457972

Hom.:

Cov.:

AF XY:

0.00000276

AC XY:

AN XY:

725426

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44712

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26128

East Asian (EAS)

AF:

0.00

AC:

AN:

39694

South Asian (SAS)

AF:

0.0000232

AC:

AN:

86238

European-Finnish (FIN)

AF:

0.00

AC:

AN:

49692

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5762

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111920

Other (OTH)

AF:

0.00

AC:

AN:

60346

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.625

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.069

BayesDel_addAF

Benign

-0.29

BayesDel_noAF

Benign

-0.65

CADD

Benign

(source)

DANN

Benign

0.96

DEOGEN2

Benign

0.17

Eigen

Benign

-0.53

Eigen_PC

Benign

-0.37

FATHMM_MKL

Benign

0.60

LIST_S2

Benign

0.76

M_CAP

Benign

0.0036

MetaRNN

Benign

0.072

MetaSVM

Benign

-0.99

MutationAssessor

Benign

-0.18

PhyloP100

2.1

PrimateAI

Benign

0.46

PROVEAN

Benign

-0.70

REVEL

Benign

0.034

Sift

Benign

0.36

Sift4G

Benign

0.41

Polyphen

0.0

Vest4

0.092

MutPred

0.29

Gain of helix (P = 0.0034)

MVP

0.25

MPC

0.41

ClinPred

0.25

GERP RS

0.11

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.065

gMVP

0.28

Mutation Taster

=87/13

polymorphism

(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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over