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GeneBe

9-128166258-T-C

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM1BP4_ModerateBS2

The NM_001131016.2(CIZ1):c.2636A>G(p.Lys879Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000814 in 1,473,386 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 Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000014 ( 0 hom., cov: 31)
Exomes 𝑓: 0.0000075 ( 0 hom. )

Consequence

CIZ1
NM_001131016.2 missense

Scores

2
6
9

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.20
Variant links:
Genes affected
CIZ1 (HGNC:16744): (CDKN1A interacting zinc finger protein 1) The protein encoded by this gene is a zinc finger DNA binding protein that interacts with CIP1, part of a complex with cyclin E. The encoded protein may regulate the cellular localization of CIP1. Several transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Apr 2012]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -4 ACMG points.

PM1
In a cross_link Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in SUMO2) (size 0) in uniprot entity CIZ1_HUMAN
BP4
Computational evidence support a benign effect (MetaRNN=0.19569823).
BS2
High AC in GnomAdExome4 at 10 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
CIZ1NM_001131016.2 linkuse as main transcriptc.2636A>G p.Lys879Arg missense_variant 17/17 ENST00000372938.10

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
CIZ1ENST00000372938.10 linkuse as main transcriptc.2636A>G p.Lys879Arg missense_variant 17/171 NM_001131016.2 P2Q9ULV3-1

Frequencies

GnomAD3 genomes
AF:
0.0000136
AC:
2
AN:
147496
Hom.:
0
Cov.:
31
show subpopulations
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:
0.000458
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD4 exome
AF:
0.00000754
AC:
10
AN:
1325890
Hom.:
0
Cov.:
36
AF XY:
0.00000614
AC XY:
4
AN XY:
651074
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000315
Gnomad4 SAS exome
AF:
0.0000130
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.000151
GnomAD4 genome
AF:
0.0000136
AC:
2
AN:
147496
Hom.:
0
Cov.:
31
AF XY:
0.0000139
AC XY:
1
AN XY:
71976
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.000458
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Asia WGS
AF:
0.000289
AC:
1
AN:
3478

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Dystonic disorder Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingInvitaeOct 18, 2022In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 935965). This variant has not been reported in the literature in individuals affected with CIZ1-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces lysine, which is basic and polar, with arginine, which is basic and polar, at codon 879 of the CIZ1 protein (p.Lys879Arg). -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.13
BayesDel_addAF
Benign
-0.098
T
BayesDel_noAF
Benign
-0.38
CADD
Pathogenic
28
DANN
Uncertain
1.0
Eigen
Uncertain
0.46
Eigen_PC
Uncertain
0.44
FATHMM_MKL
Uncertain
0.76
D
LIST_S2
Uncertain
0.91
D;D;D;D;D;.;D;.;D;D
M_CAP
Benign
0.027
D
MetaRNN
Benign
0.20
T;T;T;T;T;T;T;T;T;T
MetaSVM
Benign
-0.64
T
MutationTaster
Benign
1.0
D;N;N;N;N;N;N;N;N;N
PrimateAI
Uncertain
0.53
T
PROVEAN
Benign
-1.4
N;.;N;.;.;N;N;N;.;N
REVEL
Benign
0.075
Sift
Pathogenic
0.0
D;.;D;.;.;D;D;D;.;D
Sift4G
Pathogenic
0.0
D;D;D;D;D;D;D;D;D;D
Polyphen
1.0
D;.;D;.;.;D;D;D;D;.
Vest4
0.30
MutPred
0.14
.;.;.;.;.;.;.;Loss of ubiquitination at K879 (P = 0.003);Loss of ubiquitination at K879 (P = 0.003);.;
MVP
0.57
MPC
0.85
ClinPred
0.88
D
GERP RS
4.5
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.24
gMVP
0.31

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs943403155; hg19: chr9-130928537; API