chr20-417604-G-A

Variant names:

• chr20-417604-G-A
• rs148091459
• NM_031229.4:c.246G>A

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6_Very_Strong BP7

The NM_031229.4(RBCK1):​c.246G>A​(p.Ala82Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000201 in 1,613,834 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00034 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00019 (0 hom.)
• Consequence: RBCK1 NM_031229.4 synonymous
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -1.04
• 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
• 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (REVEL=0.015).
• BP6: Variant 20-417604-G-A is Benign according to our data. Variant chr20-417604-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 541951.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.04 with no splicing effect.

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.246G>A	p.Ala82Ala	synonymous	Exon 3 of 12	NP_112506.2	Q9BYM8-1
	RBCK1	NM_001410770.1		c.297G>A	p.Ala99Ala	synonymous	Exon 3 of 12	NP_001397699.1	A0A8V8TMZ2
	RBCK1	NM_006462.6		c.120G>A	p.Ala40Ala	synonymous	Exon 2 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.246G>A	p.Ala82Ala	synonymous	Exon 3 of 12	ENSP00000348632.6	Q9BYM8-1
	RBCK1	ENST00000353660.7	TSL:1	c.120G>A	p.Ala40Ala	synonymous	Exon 2 of 11	ENSP00000254960.5	Q9BYM8-3
	RBCK1	ENST00000382181.2	TSL:1	n.120G>A		non_coding_transcript_exon	Exon 2 of 10	ENSP00000371616.3	Q9BYM8-4

Frequencies

GnomAD3 genomes AF: 0.000335 AC: 51 AN: 152216 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000651

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000338

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000135 AC: 34 AN: 251066 AF XY: 0.000125

Gnomad AFR exome AF: 0.000308

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.0000993

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000238

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000187 AC: 274 AN: 1461618 Hom.: 0 Cov.: 32 AF XY: 0.000172 AC XY: 125 AN XY: 727084

African (AFR) AF: 0.000478 AC: 16 AN: 33480

American (AMR) AF: 0.0000224 AC: 1 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.00 AC: 0 AN: 86252

European-Finnish (FIN) AF: 0.0000188 AC: 1 AN: 53282

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5764

European-Non Finnish (NFE) AF: 0.000212 AC: 236 AN: 1111904

Other (OTH) AF: 0.000298 AC: 18 AN: 60388

GnomAD4 genome AF: 0.000335 AC: 51 AN: 152216 Hom.: 0 Cov.: 33 AF XY: 0.000363 AC XY: 27 AN XY: 74364

African (AFR) AF: 0.000651 AC: 27 AN: 41444

American (AMR) AF: 0.00 AC: 0 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5198

South Asian (SAS) AF: 0.00 AC: 0 AN: 4836

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000338 AC: 23 AN: 68042

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.000327 Hom.: 0

Bravo AF: 0.000332

EpiCase AF: 0.000164

EpiControl AF: 0.00

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)
-	-	1	Polyglucosan body myopathy type 1 (1)
-	-	1	RBCK1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.68
CADD	Benign	9.2
DANN	Benign	0.68
PhyloP100		-1.0

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: rs148091459; hg19: chr20-398248; COSMIC: COSV62292005; COSMIC: COSV62292005;