rs41281892

Variant names:

• chr20-410002-G-A
• rs41281892
• NM_031229.4:c.144G>A

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_031229.4(RBCK1):​c.144G>A​(p.Glu48Glu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0387 in 1,614,060 control chromosomes in the GnomAD database, including 1,427 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.030 (94 hom., cov: 32)
  • Exomes 𝑓: 0.040 (1333 hom.)
• Consequence: RBCK1 NM_031229.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 1.01
• Publications: 4 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: Benign. The variant received -19 ACMG points.

• BP4: Computational evidence support a benign effect (REVEL=0.033).
• BP6: Variant 20-410002-G-A is Benign according to our data. Variant chr20-410002-G-A is described in ClinVar as Benign. ClinVar VariationId is 475182.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.01 with no splicing effect.
• BA1: GnomAdExome4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0501 is higher than 0.05.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RBCK1	NM_031229.4	MANE Select	c.144G>A	p.Glu48Glu	synonymous	Exon 2 of 12	NP_112506.2
	RBCK1	NM_001410770.1		c.195G>A	p.Glu65Glu	synonymous	Exon 2 of 12	NP_001397699.1
	RBCK1	NM_001323960.2		c.144G>A	p.Glu48Glu	synonymous	Exon 2 of 3	NP_001310889.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RBCK1	ENST00000356286.10	TSL:1 MANE Select	c.144G>A	p.Glu48Glu	synonymous	Exon 2 of 12	ENSP00000348632.6
	RBCK1	ENST00000475269.5	TSL:1	c.144G>A	p.Glu48Glu	synonymous	Exon 2 of 3	ENSP00000417173.1
	RBCK1	ENST00000382214.7	TSL:1	n.144G>A		non_coding_transcript_exon	Exon 2 of 12	ENSP00000371649.3

Frequencies

GnomAD3 genomes AF: 0.0304 AC: 4624 AN: 152152 Hom.: 94 Cov.: 32

Gnomad AFR AF: 0.00685

Gnomad AMI AF: 0.0362

Gnomad AMR AF: 0.0219

Gnomad ASJ AF: 0.0464

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.0427

Gnomad FIN AF: 0.0620

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.0423

Gnomad OTH AF: 0.0292

GnomAD2 exomes AF: 0.0354 AC: 8875 AN: 251028 AF XY: 0.0378

Gnomad AFR exome AF: 0.00646

Gnomad AMR exome AF: 0.0157

Gnomad ASJ exome AF: 0.0453

Gnomad EAS exome AF: 0.000109

Gnomad FIN exome AF: 0.0556

Gnomad NFE exome AF: 0.0420

Gnomad OTH exome AF: 0.0392

GnomAD4 exome AF: 0.0396 AC: 57825 AN: 1461790 Hom.: 1333 Cov.: 31 AF XY: 0.0399 AC XY: 29032 AN XY: 727200

African (AFR) AF: 0.00609 AC: 204 AN: 33480

American (AMR) AF: 0.0167 AC: 747 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.0440 AC: 1150 AN: 26132

East Asian (EAS) AF: 0.000126 AC: 5 AN: 39700

South Asian (SAS) AF: 0.0514 AC: 4431 AN: 86254

European-Finnish (FIN) AF: 0.0569 AC: 3037 AN: 53404

Middle Eastern (MID) AF: 0.0310 AC: 179 AN: 5768

European-Non Finnish (NFE) AF: 0.0411 AC: 45740 AN: 1111942

Other (OTH) AF: 0.0386 AC: 2332 AN: 60388

GnomAD4 genome AF: 0.0303 AC: 4621 AN: 152270 Hom.: 94 Cov.: 32 AF XY: 0.0302 AC XY: 2249 AN XY: 74450

African (AFR) AF: 0.00683 AC: 284 AN: 41556

American (AMR) AF: 0.0218 AC: 334 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.0464 AC: 161 AN: 3468

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5184

South Asian (SAS) AF: 0.0425 AC: 205 AN: 4820

European-Finnish (FIN) AF: 0.0620 AC: 658 AN: 10606

Middle Eastern (MID) AF: 0.0204 AC: 6 AN: 294

European-Non Finnish (NFE) AF: 0.0423 AC: 2878 AN: 68024

Other (OTH) AF: 0.0289 AC: 61 AN: 2110

Alfa AF: 0.0372 Hom.: 252

Bravo AF: 0.0264

Asia WGS AF: 0.0180 AC: 64 AN: 3478

EpiCase AF: 0.0390

EpiControl AF: 0.0392

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Polyglucosan body myopathy type 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.69
CADD	Benign	7.8
DANN	Benign	0.56
PhyloP100		1.0
PromoterAI		-0.016	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism (auto)

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: rs41281892; hg19: chr20-390646;