rs377605009
Positions:
Variant summary
Our verdict is Benign. Variant got -7 ACMG points: 2P and 9B. PM2BP4_StrongBP6BS1
The NM_031229.4(RBCK1):āc.782A>Gā(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: š 0.00048 ( 0 hom., cov: 26)
Exomes š: 0.00038 ( 0 hom. )
Consequence
RBCK1
NM_031229.4 missense
NM_031229.4 missense
Scores
11
8
Clinical Significance
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]
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ACMG classification
Classification made for transcript
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: 73AN: 148704Hom.: 0 Cov.: 26
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GnomAD3 exomes AF: 0.000750 AC: 120AN: 160082Hom.: 0 AF XY: 0.000756 AC XY: 65AN XY: 86008
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GnomAD4 exome AF: 0.000385 AC: 541AN: 1405874Hom.: 0 Cov.: 32 AF XY: 0.000405 AC XY: 281AN XY: 694356
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GnomAD4 genome ? AF: 0.000484 AC: 72AN: 148820Hom.: 0 Cov.: 26 AF XY: 0.000399 AC XY: 29AN XY: 72630
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:2Benign:2
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Feb 01, 2017 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Jan 17, 2024 | Observed in the homozygous state in a fetus with dilated heart and somewhat tortuous PDA who was also found to have variants in additional genes (PMID: 36068917); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 36068917) - |
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:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Uncertain
D;.
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D;D
M_CAP
Benign
T
MetaRNN
Benign
T;T
MetaSVM
Benign
T
MutationAssessor
Uncertain
M;.
MutationTaster
Benign
D;D;D
PrimateAI
Uncertain
T
PROVEAN
Uncertain
D;D
REVEL
Benign
Sift
Uncertain
D;D
Sift4G
Uncertain
D;D
Polyphen
P;P
Vest4
MVP
MPC
ClinPred
T
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at