Genetic Variant NM_031229.4:c.746A>T (chr20-419721-A-T) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_031229.4(RBCK1):c.746A>T(p.Gln249Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000284 in 1,406,946 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. Q249R) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000028 ( 0 hom. )

Consequence

RBCK1
NM_031229.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 4.16

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
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: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

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	UniProt
RBCK1	NM_031229.4	MANE Select	c.746A>T	p.Gln249Leu	missense	Exon 6 of 12	NP_112506.2	Q9BYM8-1
RBCK1	NM_001410770.1		c.797A>T	p.Gln266Leu	missense	Exon 6 of 12	NP_001397699.1	A0A8V8TMZ2
RBCK1	NM_006462.6		c.620A>T	p.Gln207Leu	missense	Exon 5 of 11	NP_006453.1	Q9BYM8-3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
RBCK1	ENST00000356286.10	TSL:1 MANE Select	c.746A>T	p.Gln249Leu	missense	Exon 6 of 12	ENSP00000348632.6	Q9BYM8-1
RBCK1	ENST00000353660.7	TSL:1	c.620A>T	p.Gln207Leu	missense	Exon 5 of 11	ENSP00000254960.5	Q9BYM8-3
RBCK1	ENST00000382181.2	TSL:1	n.620A>T		non_coding_transcript_exon	Exon 5 of 10	ENSP00000371616.3	Q9BYM8-4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000284

AC:

AN:

1406946

Hom.:

Cov.:

AF XY:

0.00000287

AC XY:

AN XY:

695968

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32360

American (AMR)

AF:

0.00

AC:

AN:

38086

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25260

East Asian (EAS)

AF:

0.00

AC:

AN:

36978

South Asian (SAS)

AF:

0.00

AC:

AN:

80590

European-Finnish (FIN)

AF:

0.00

AC:

AN:

41450

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5698

European-Non Finnish (NFE)

AF:

0.00000368

AC:

AN:

1087984

Other (OTH)

AF:

0.00

AC:

AN:

58540

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

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

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.086

BayesDel_addAF

Benign

-0.092

BayesDel_noAF

Benign

-0.37

CADD

Benign

(source)

DANN

Benign

0.97

DEOGEN2

Uncertain

0.53

Eigen

Uncertain

0.37

Eigen_PC

Uncertain

0.33

FATHMM_MKL

Uncertain

0.94

LIST_S2

Benign

0.75

M_CAP

Benign

0.029

MetaRNN

Uncertain

0.42

MetaSVM

Benign

-0.86

MutationAssessor

Benign

1.8

PhyloP100

4.2

PrimateAI

Uncertain

0.64

PROVEAN

Uncertain

-2.8

REVEL

Benign

0.13

Sift

Uncertain

0.013

Sift4G

Uncertain

0.044

Polyphen

0.069

Vest4

0.64

MutPred

0.29

Loss of helix (P = 0.028)

MVP

0.41

MPC

0.44

ClinPred

0.91

GERP RS

3.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.9

Varity_R

0.19

gMVP

0.85

Mutation Taster

=40/60

disease causing

(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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over