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GeneBe

9-128166268-T-C

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_001131016.2(CIZ1):c.2626A>G(p.Thr876Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000387 in 1,551,952 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 31)
Exomes 𝑓: 0.0000036 ( 0 hom. )

Consequence

CIZ1
NM_001131016.2 missense

Scores

2
15

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.115
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]

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.054417074).
BS2
High AC in GnomAdExome4 at 5 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
CIZ1NM_001131016.2 linkuse as main transcriptc.2626A>G p.Thr876Ala missense_variant 17/17 ENST00000372938.10

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
CIZ1ENST00000372938.10 linkuse as main transcriptc.2626A>G p.Thr876Ala missense_variant 17/171 NM_001131016.2 P2Q9ULV3-1

Frequencies

GnomAD3 genomes
AF:
0.00000660
AC:
1
AN:
151468
Hom.:
0
Cov.:
31
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000657
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000221
AC:
4
AN:
181368
Hom.:
0
AF XY:
0.0000104
AC XY:
1
AN XY:
96394
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.000150
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000357
AC:
5
AN:
1400484
Hom.:
0
Cov.:
45
AF XY:
0.00000290
AC XY:
2
AN XY:
689564
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.000134
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.00000660
AC:
1
AN:
151468
Hom.:
0
Cov.:
31
AF XY:
0.0000135
AC XY:
1
AN XY:
73964
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.0000657
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.0000113

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 testingInvitaeDec 11, 2023This sequence change replaces threonine, which is neutral and polar, with alanine, which is neutral and non-polar, at codon 876 of the CIZ1 protein (p.Thr876Ala). This variant is present in population databases (no rsID available, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with CIZ1-related conditions. ClinVar contains an entry for this variant (Variation ID: 2202278). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The alanine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. In 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. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.090
BayesDel_addAF
Benign
-0.51
T
BayesDel_noAF
Benign
-0.72
CADD
Benign
15
DANN
Benign
0.97
Eigen
Benign
-0.94
Eigen_PC
Benign
-1.1
FATHMM_MKL
Benign
0.058
N
LIST_S2
Benign
0.56
T;T;T;T;T;.;T;.;T;T
M_CAP
Benign
0.0083
T
MetaRNN
Benign
0.054
T;T;T;T;T;T;T;T;T;T
MetaSVM
Benign
-1.0
T
MutationTaster
Benign
1.0
N;N;N;N;N;N;N;N;N;N
PrimateAI
Benign
0.39
T
PROVEAN
Benign
-0.95
N;.;N;.;.;N;N;N;.;N
REVEL
Benign
0.15
Sift
Uncertain
0.025
D;.;D;.;.;D;D;D;.;D
Sift4G
Uncertain
0.035
D;D;D;D;D;D;D;D;D;D
Polyphen
0.63
P;.;P;.;.;P;P;P;P;.
Vest4
0.063
MutPred
0.12
.;.;.;.;.;.;.;Loss of phosphorylation at T876 (P = 0.0017);Loss of phosphorylation at T876 (P = 0.0017);.;
MVP
0.35
MPC
0.27
ClinPred
0.081
T
GERP RS
-3.8
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.1
Varity_R
0.039
gMVP
0.27

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: rs1042230806; hg19: chr9-130928547; API