20-409899-G-C

Variant names:

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

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>C​(p.Ser14Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,204 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. S14N) has been classified as Uncertain significance.

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
• Consequence: RBCK1 NM_031229.4 missense
• Clinical Significance: Not reported in ClinVar
• 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=0.04729569).

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>C	p.Ser14Thr	missense	Exon 2 of 12	NP_112506.2	Q9BYM8-1
	RBCK1	NM_001410770.1		c.92G>C	p.Ser31Thr	missense	Exon 2 of 12	NP_001397699.1	A0A8V8TMZ2
	RBCK1	NM_001323960.2		c.41G>C	p.Ser14Thr	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>C	p.Ser14Thr	missense	Exon 2 of 12	ENSP00000348632.6	Q9BYM8-1
	RBCK1	ENST00000475269.5	TSL:1	c.41G>C	p.Ser14Thr	missense	Exon 2 of 3	ENSP00000417173.1	A6PVJ6
	RBCK1	ENST00000353660.7	TSL:1	c.41+1120G>C		intron	N/A	ENSP00000254960.5	Q9BYM8-3

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152204 Hom.: 0 Cov.: 32

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: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 31

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152204 Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1 AN XY: 74362

African (AFR) AF: 0.00 AC: 0 AN: 41452

American (AMR) AF: 0.00 AC: 0 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68036

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.073
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	16
DANN	Benign	0.93
DEOGEN2	Benign	0.029	T
Eigen	Benign	-0.68
Eigen_PC	Benign	-0.61
FATHMM_MKL	Benign	0.13	N
LIST_S2	Benign	0.74	T
M_CAP	Benign	0.0070	T
MetaRNN	Benign	0.047	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	2.0	M
PhyloP100		0.25
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-0.86	N
REVEL	Benign	0.048
Sift	Benign	0.55	T
Sift4G	Benign	0.23	T
Polyphen		0.026	B
Vest4		0.25
MutPred		0.26		Loss of phosphorylation at S14 (P = 0.0517)
MVP		0.36
MPC		0.40
ClinPred		0.040	T
GERP RS		2.6
PromoterAI		-0.052	Neutral
Varity_R		0.074
gMVP		0.18
Mutation Taster		=96/4	polymorphism

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

Other links and lift over

dbSNP: rs1471676178; hg19: chr20-390543;