20-409908-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_031229.4(RBCK1):c.50G>A(p.Arg17Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000434 in 1,613,970 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 0.000072 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000040 (0 hom.)
• Consequence: RBCK1 NM_031229.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.93

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]

ACMG classification

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=0.22873732).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RBCK1	NM_031229.4	c.50G>A	p.Arg17Gln	missense_variant	2/12	ENST00000356286.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RBCK1	ENST00000356286.10	c.50G>A	p.Arg17Gln	missense_variant	2/12	1	NM_031229.4	P1

Frequencies

GnomAD3 genomes AF: 0.0000723 AC: 11 AN: 152158 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

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: 0.000132

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000678 AC: 17 AN: 250784 Hom.: 0 AF XY: 0.0000664 AC XY: 9 AN XY: 135644

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000272

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000970

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.0000404 AC: 59 AN: 1461812 Hom.: 0 Cov.: 31 AF XY: 0.0000426 AC XY: 31 AN XY: 727204

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000151

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.0000396

Gnomad4 OTH exome AF: 0.0000993

GnomAD4 genome AF: 0.0000723 AC: 11 AN: 152158 Hom.: 0 Cov.: 32 AF XY: 0.0000942 AC XY: 7 AN XY: 74322

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000132

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000100 Hom.: 0

Bravo AF: 0.0000491

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.0000659 AC: 8

EpiCase AF: 0.00

EpiControl AF: 0.000119

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Polyglucosan body myopathy type 1 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Aug 15, 2022

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 17 of the RBCK1 protein (p.Arg17Gln). This variant is present in population databases (rs200757913, gnomAD 0.02%). 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: 858404). 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	0.073
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.30
Cadd	Benign	23
Dann	Pathogenic	1.0
DEOGEN2	Benign	0.019	T;T;T;T
Eigen	Benign	0.16
Eigen_PC	Benign	0.16
FATHMM_MKL	Benign	0.51	D
LIST_S2	Uncertain	0.92	D;D;D;D
M_CAP	Benign	0.0081	T
MetaRNN	Benign	0.23	T;T;T;T
MetaSVM	Benign	-0.99	T
MutationTaster	Benign	1.0	D;D;D;N;N
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-0.25	N;N;N;N
REVEL	Benign	0.097
Sift	Benign	0.31	T;T;D;T
Sift4G	Pathogenic	0.0	D;T;D;D
Polyphen		0.96	.;D;.;.
Vest4		0.27, 0.37
MVP		0.53
MPC		0.52
ClinPred		0.080	T
GERP RS		4.7
Varity_R		0.090
gMVP		0.27

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

Other links and lift over

dbSNP: rs200757913; hg19: chr20-390552;