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GeneBe

9-128166252-G-A

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_001131016.2(CIZ1):c.2642C>T(p.Thr881Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000153 in 1,437,112 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. T881T) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0000069 ( 0 hom., cov: 31)
Exomes 𝑓: 0.000016 ( 0 hom. )

Consequence

CIZ1
NM_001131016.2 missense

Scores

3
14

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.813
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 Likely_benign. Variant got -6 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.11300191).
BS2
High AC in GnomAdExome4 at 21 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
CIZ1NM_001131016.2 linkuse as main transcriptc.2642C>T p.Thr881Met missense_variant 17/17 ENST00000372938.10

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
CIZ1ENST00000372938.10 linkuse as main transcriptc.2642C>T p.Thr881Met missense_variant 17/171 NM_001131016.2 P2Q9ULV3-1

Frequencies

GnomAD3 genomes
AF:
0.00000690
AC:
1
AN:
144868
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:
0.000232
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:
0.00000600
AC:
1
AN:
166764
Hom.:
0
AF XY:
0.0000114
AC XY:
1
AN XY:
87882
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.0000711
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:
0.0000163
AC:
21
AN:
1292110
Hom.:
0
Cov.:
33
AF XY:
0.0000174
AC XY:
11
AN XY:
632018
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.000328
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000795
Gnomad4 OTH exome
AF:
0.0000196
GnomAD4 genome
AF:
0.00000690
AC:
1
AN:
145002
Hom.:
0
Cov.:
31
AF XY:
0.00
AC XY:
0
AN XY:
70618
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.000232
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000521
Hom.:
0
Bravo
AF:
0.00000756
ExAC
AF:
0.0000250
AC:
3
Asia WGS
AF:
0.000577
AC:
2
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 testingInvitaeNov 27, 2023This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 881 of the CIZ1 protein (p.Thr881Met). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has not been reported in the literature in individuals affected with CIZ1-related conditions. 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 methionine 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
0.11
BayesDel_addAF
Benign
-0.23
T
BayesDel_noAF
Benign
-0.57
CADD
Benign
23
DANN
Uncertain
1.0
Eigen
Benign
-0.32
Eigen_PC
Benign
-0.35
FATHMM_MKL
Benign
0.37
N
LIST_S2
Uncertain
0.91
D;D;D;D;D;.;D;.;D;D
M_CAP
Benign
0.0093
T
MetaRNN
Benign
0.11
T;T;T;T;T;T;T;T;T;T
MetaSVM
Benign
-1.1
T
MutationTaster
Benign
1.0
D;N;N;N;N;N;N;N;N;N
PrimateAI
Benign
0.41
T
PROVEAN
Benign
-1.9
N;.;N;.;.;N;N;N;.;N
REVEL
Benign
0.14
Sift
Uncertain
0.0070
D;.;D;.;.;D;D;D;.;D
Sift4G
Benign
0.11
T;T;T;T;T;T;T;T;T;T
Polyphen
1.0
D;.;D;.;.;D;D;D;D;.
Vest4
0.17
MutPred
0.18
.;.;.;.;.;.;.;Loss of phosphorylation at T881 (P = 0.0064);Loss of phosphorylation at T881 (P = 0.0064);.;
MVP
0.36
MPC
0.39
ClinPred
0.21
T
GERP RS
1.3
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.019
gMVP
0.28

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: rs745411073; hg19: chr9-130928531; COSMIC: COSV52974974; COSMIC: COSV52974974; API