rs727503762

Variant names:

• chr20-419439-C-T
• rs727503762
• NM_031229.4:c.553C>T

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PVS1 PM2 PP5

The NM_031229.4(RBCK1):​c.553C>T​(p.Gln185*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 33)
• Consequence: RBCK1 NM_031229.4 stop_gained
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 0.859
• Publications: 13 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: 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

ACMG classification

Our verdict: Pathogenic. The variant received 11 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 20-419439-C-T is Pathogenic according to our data. Variant chr20-419439-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 140623.Status of the report is no_assertion_criteria_provided, 0 stars.

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.553C>T	p.Gln185*	stop_gained	Exon 5 of 12	NP_112506.2	Q9BYM8-1
	RBCK1	NM_001410770.1		c.604C>T	p.Gln202*	stop_gained	Exon 5 of 12	NP_001397699.1	A0A8V8TMZ2
	RBCK1	NM_006462.6		c.427C>T	p.Gln143*	stop_gained	Exon 4 of 11	NP_006453.1	Q9BYM8-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RBCK1	ENST00000356286.10	TSL:1 MANE Select	c.553C>T	p.Gln185*	stop_gained	Exon 5 of 12	ENSP00000348632.6	Q9BYM8-1
	RBCK1	ENST00000353660.7	TSL:1	c.427C>T	p.Gln143*	stop_gained	Exon 4 of 11	ENSP00000254960.5	Q9BYM8-3
	RBCK1	ENST00000382181.2	TSL:1	n.427C>T		non_coding_transcript_exon	Exon 4 of 10	ENSP00000371616.3	Q9BYM8-4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Polyglucosan body myopathy 1 with immunodeficiency (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.59	D
BayesDel_noAF	Pathogenic	0.24
CADD	Pathogenic	36
DANN	Benign	0.96
Eigen	Benign	0.11
Eigen_PC	Benign	-0.25
FATHMM_MKL	Benign	0.18	N
PhyloP100		0.86
Vest4		0.74
GERP RS		0.72
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=4/196	disease causing (ClinVar)

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: rs727503762; hg19: chr20-400083;