rs727503764

Variant names:

• chr20-421006-CGTGA-C
• rs727503764
• NM_031229.4:c.896_899delAGTG

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_031229.4(RBCK1):​c.896_899delAGTG​(p.Glu299ValfsTer46) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000148 in 1,415,042 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 27)
  • Exomes 𝑓: 0.000015 (0 hom.)
• Consequence: RBCK1 NM_031229.4 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 9.69
• Publications: 7 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 18 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 20-421006-CGTGA-C is Pathogenic according to our data. Variant chr20-421006-CGTGA-C is described in ClinVar as Pathogenic. ClinVar VariationId is 140625.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 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.896_899delAGTG	p.Glu299ValfsTer46	frameshift	Exon 7 of 12	NP_112506.2	Q9BYM8-1
	RBCK1	NM_001410770.1		c.947_950delAGTG	p.Glu316ValfsTer46	frameshift	Exon 7 of 12	NP_001397699.1	A0A8V8TMZ2
	RBCK1	NM_006462.6		c.770_773delAGTG	p.Glu257ValfsTer46	frameshift	Exon 6 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.896_899delAGTG	p.Glu299ValfsTer46	frameshift	Exon 7 of 12	ENSP00000348632.6	Q9BYM8-1
	RBCK1	ENST00000353660.7	TSL:1	c.770_773delAGTG	p.Glu257ValfsTer46	frameshift	Exon 6 of 11	ENSP00000254960.5	Q9BYM8-3
	RBCK1	ENST00000382181.2	TSL:1	n.631-1117_631-1114delAGTG		intron	N/A	ENSP00000371616.3	Q9BYM8-4

Frequencies

GnomAD3 genomes Cov.: 27

GnomAD2 exomes AF: 0.0000114 AC: 2 AN: 175738 AF XY: 0.0000211

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000357

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000214

GnomAD4 exome AF: 0.0000148 AC: 21 AN: 1415042 Hom.: 0 AF XY: 0.0000143 AC XY: 10 AN XY: 699810

African (AFR) AF: 0.00 AC: 0 AN: 32350

American (AMR) AF: 0.0000256 AC: 1 AN: 39088

Ashkenazi Jewish (ASJ) AF: 0.0000396 AC: 1 AN: 25266

East Asian (EAS) AF: 0.00 AC: 0 AN: 37096

South Asian (SAS) AF: 0.0000372 AC: 3 AN: 80644

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48164

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4868

European-Non Finnish (NFE) AF: 0.0000138 AC: 15 AN: 1089040

Other (OTH) AF: 0.0000171 AC: 1 AN: 58526

GnomAD4 genome Cov.: 27

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
4	-	-	Polyglucosan body myopathy type 1 (4)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		9.7
Mutation Taster		=3/197	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: rs727503764; hg19: chr20-401650;