chr20-417619-G-GGTGA

Variant names:

• chr20-417619-G-GGTGA
• rs754865819
• NM_031229.4:c.261+6_261+9dupTGAG

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PVS1_Moderate PM2

The ENST00000356286.10(RBCK1):​c.261_261+1insGTGA variant causes a splice donor, intron change. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 33)
• Consequence: RBCK1 ENST00000356286.10 splice_donor, intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.09
• 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: 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: Uncertain_significance. The variant received 4 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.06131768 fraction of the gene. Cryptic splice site detected, with MaxEntScore 10, offset of 0 (no position change), new splice context is: atgGTgagt. Cryptic site results in inframe change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.
• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000356286.10. 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.261+6_261+9dupTGAG		intron	N/A	NP_112506.2	Q9BYM8-1
	RBCK1	NM_001410770.1		c.312+6_312+9dupTGAG		intron	N/A	NP_001397699.1	A0A8V8TMZ2
	RBCK1	NM_006462.6		c.135+6_135+9dupTGAG		intron	N/A	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.261_261+1insGTGA		splice_donor intron	N/A	ENSP00000348632.6	Q9BYM8-1
	RBCK1	ENST00000353660.7	TSL:1	c.135_135+1insGTGA		splice_donor intron	N/A	ENSP00000254960.5	Q9BYM8-3
	RBCK1	ENST00000382181.2	TSL:1	n.135_135+1insGTGA		splice_donor intron	N/A	ENSP00000371616.3	Q9BYM8-4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		7.1

Splicing

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs754865819; hg19: chr20-398263;