chr20-409899-G-A

Variant names:

• chr20-409899-G-A
• rs1471676178
• NM_031229.4:c.41G>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_031229.4(RBCK1):​c.41G>A​(p.Ser14Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,790 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: RBCK1 NM_031229.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 0.250
• Publications: 0 publications found

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: PanelApp Australia, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• 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

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.049026817).

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RBCK1	NM_031229.4	MANE Select	c.41G>A	p.Ser14Asn	missense	Exon 2 of 12	NP_112506.2	Q9BYM8-1
	RBCK1	NM_001410770.1		c.92G>A	p.Ser31Asn	missense	Exon 2 of 12	NP_001397699.1	A0A8V8TMZ2
	RBCK1	NM_001323960.2		c.41G>A	p.Ser14Asn	missense	Exon 2 of 3	NP_001310889.1	A6PVJ6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RBCK1	ENST00000356286.10	TSL:1 MANE Select	c.41G>A	p.Ser14Asn	missense	Exon 2 of 12	ENSP00000348632.6	Q9BYM8-1
	RBCK1	ENST00000475269.5	TSL:1	c.41G>A	p.Ser14Asn	missense	Exon 2 of 3	ENSP00000417173.1	A6PVJ6
	RBCK1	ENST00000353660.7	TSL:1	c.41+1120G>A		intron	N/A	ENSP00000254960.5	Q9BYM8-3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251022 AF XY: 0.00000737

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000881

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461790 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727184

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86246

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53378

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111974

Other (OTH) AF: 0.00 AC: 0 AN: 60392

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Inborn genetic diseases (1)
-	1	-	Polyglucosan body myopathy type 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.083
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.57
CADD	Benign	16
DANN	Uncertain	0.98
DEOGEN2	Benign	0.027	T
Eigen	Benign	-0.70
Eigen_PC	Benign	-0.62
FATHMM_MKL	Benign	0.079	N
LIST_S2	Benign	0.79	T
M_CAP	Benign	0.0059	T
MetaRNN	Benign	0.049	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	2.0	M
PhyloP100		0.25
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-0.57	N
REVEL	Benign	0.030
Sift	Benign	0.50	T
Sift4G	Benign	0.20	T
Polyphen		0.026	B
Vest4		0.16
MutPred		0.26		Loss of phosphorylation at S14 (P = 0.0302)
MVP		0.36
MPC		0.38
ClinPred		0.042	T
GERP RS		2.6
PromoterAI		-0.023	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.045
gMVP		0.21
Mutation Taster		=95/5	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1471676178; hg19: chr20-390543;