rs377605009

chr20-420896-A-Gchr20-420896-A-T

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 2P and 9B. PM2 BP4_Strong BP6 BS1

The NM_031229.4(RBCK1):c.782A>G(p.Asn261Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000394 in 1,554,694 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 Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00048 (0 hom., cov: 26)
  • Exomes 𝑓: 0.00038 (0 hom.)
• Consequence: RBCK1 NM_031229.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:2
• Conservation: PhyloP100: 4.90

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]

ACMG classification

Verdict is Benign. Variant got -7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.010425061).
• BP6: Variant 20-420896-A-G is Benign according to our data. Variant chr20-420896-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 475186.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Likely_benign=2}.
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.000484 (72/148820) while in subpopulation AMR AF= 0.00113 (17/15018). AF 95% confidence interval is 0.000721. There are 0 homozygotes in gnomad4. There are 29 alleles in male gnomad4 subpopulation. Median coverage is 26. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RBCK1	NM_031229.4	c.782A>G	p.Asn261Ser	missense_variant	7/12	ENST00000356286.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RBCK1	ENST00000356286.10	c.782A>G	p.Asn261Ser	missense_variant	7/12	1	NM_031229.4	P1

Frequencies

GnomAD3 genomes AF: 0.000491 AC: 73 AN: 148704 Hom.: 0 Cov.: 26

Gnomad AFR AF: 0.000199

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00113

Gnomad ASJ AF: 0.00725

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00955

Gnomad NFE AF: 0.000283

Gnomad OTH AF: 0.000492

GnomAD3 exomes AF: 0.000750 AC: 120 AN: 160082 Hom.: 0 AF XY: 0.000756 AC XY: 65 AN XY: 86008

Gnomad AFR exome AF: 0.000107

Gnomad AMR exome AF: 0.000827

Gnomad ASJ exome AF: 0.00810

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000851

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000279

Gnomad OTH exome AF: 0.00246

GnomAD4 exome AF: 0.000385 AC: 541 AN: 1405874 Hom.: 0 Cov.: 32 AF XY: 0.000405 AC XY: 281 AN XY: 694356

Gnomad4 AFR exome AF: 0.000124

Gnomad4 AMR exome AF: 0.000876

Gnomad4 ASJ exome AF: 0.00948

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000100

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000169

Gnomad4 OTH exome AF: 0.00113

GnomAD4 genome AF: 0.000484 AC: 72 AN: 148820 Hom.: 0 Cov.: 26 AF XY: 0.000399 AC XY: 29 AN XY: 72630

Gnomad4 AFR AF: 0.000199

Gnomad4 AMR AF: 0.00113

Gnomad4 ASJ AF: 0.00725

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000283

Gnomad4 OTH AF: 0.000486

Alfa AF: 0.00125 Hom.: 0

Bravo AF: 0.000597

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000120 AC: 1

ExAC AF: 0.000273 AC: 31

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Sep 15, 2020	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2017	- -

Polyglucosan body myopathy type 1 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

RBCK1-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 10, 2023

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.23
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.53
Cadd	Uncertain	24
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.57	D;.
Eigen	Uncertain	0.25
Eigen_PC	Uncertain	0.32
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.90	D;D
M_CAP	Benign	0.023	T
MetaRNN	Benign	0.010	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.3	M;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.75	T
PROVEAN	Uncertain	-2.8	D;D
REVEL	Benign	0.14
Sift	Uncertain	0.0080	D;D
Sift4G	Uncertain	0.013	D;D
Polyphen		0.54	P;P
Vest4		0.48
MVP		0.37
MPC		1.1
ClinPred		0.063	T
GERP RS		4.4
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.8
Varity_R		0.13
gMVP		0.84

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs377605009; hg19: chr20-401540;