chr20-420896-A-T

Variant names:

• chr20-420896-A-T
• rs377605009
• NM_031229.4:c.782A>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001410770.1(RBCK1):​c.833A>T​(p.Asn278Ile) variant causes a missense change. The variant allele was found at a frequency of 0.00000672 in 148,820 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. N278S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0000067 (0 hom., cov: 26)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: RBCK1 NM_001410770.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.90
• Publications: 1 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, PanelApp Australia
• 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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001410770.1. 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.782A>T	p.Asn261Ile	missense	Exon 7 of 12	NP_112506.2
	RBCK1	NM_001410770.1		c.833A>T	p.Asn278Ile	missense	Exon 7 of 12	NP_001397699.1
	RBCK1	NM_006462.6		c.656A>T	p.Asn219Ile	missense	Exon 6 of 11	NP_006453.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RBCK1	ENST00000356286.10	TSL:1 MANE Select	c.782A>T	p.Asn261Ile	missense	Exon 7 of 12	ENSP00000348632.6
	RBCK1	ENST00000353660.7	TSL:1	c.656A>T	p.Asn219Ile	missense	Exon 6 of 11	ENSP00000254960.5
	RBCK1	ENST00000382214.7	TSL:1	n.782A>T		non_coding_transcript_exon	Exon 7 of 12	ENSP00000371649.3

Frequencies

GnomAD3 genomes AF: 0.00000672 AC: 1 AN: 148704 Hom.: 0 Cov.: 26

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: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000149

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1405874 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 694356

African (AFR) AF: 0.00 AC: 0 AN: 32270

American (AMR) AF: 0.00 AC: 0 AN: 36510

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25218

East Asian (EAS) AF: 0.00 AC: 0 AN: 36968

South Asian (SAS) AF: 0.00 AC: 0 AN: 79936

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48144

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4276

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1084388

Other (OTH) AF: 0.00 AC: 0 AN: 58164

GnomAD4 genome AF: 0.00000672 AC: 1 AN: 148820 Hom.: 0 Cov.: 26 AF XY: 0.0000138 AC XY: 1 AN XY: 72630

African (AFR) AF: 0.00 AC: 0 AN: 40242

American (AMR) AF: 0.00 AC: 0 AN: 15018

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3450

East Asian (EAS) AF: 0.00 AC: 0 AN: 4836

South Asian (SAS) AF: 0.00 AC: 0 AN: 4608

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10374

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 290

European-Non Finnish (NFE) AF: 0.0000149 AC: 1 AN: 67058

Other (OTH) AF: 0.00 AC: 0 AN: 2056

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.46
BayesDel_addAF	Benign	-0.020	T
BayesDel_noAF	Benign	-0.27
CADD	Pathogenic	30
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.61	D
Eigen	Uncertain	0.50
Eigen_PC	Uncertain	0.49
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.87	D
M_CAP	Benign	0.056	D
MetaRNN	Uncertain	0.69	D
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.3	M
PhyloP100		4.9
PrimateAI	Uncertain	0.79	T
PROVEAN	Pathogenic	-5.1	D
REVEL	Benign	0.24
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Polyphen		0.94	P
Vest4		0.75
MutPred		0.44		Gain of loop (P = 0.0166)
MVP		0.41
MPC		1.4
ClinPred		0.99	D
GERP RS		4.4
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.8
Varity_R		0.71
gMVP		0.93
Mutation Taster		=46/54	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.23		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.23		Position offset: 11

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

Other links and lift over

dbSNP: rs377605009; hg19: chr20-401540;