9-128166246-C-T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_001131016.2(CIZ1):c.2648G>A(p.Arg883Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000191 in 1,469,492 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 0.000056 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000015 (0 hom.)
• Consequence: CIZ1 NM_001131016.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.80

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]

ACMG classification

Verdict is Benign. Variant got -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.019570619).
• BS2: High AC in GnomAd at 8 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CIZ1	NM_001131016.2	c.2648G>A	p.Arg883Gln	missense_variant	17/17	ENST00000372938.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CIZ1	ENST00000372938.10	c.2648G>A	p.Arg883Gln	missense_variant	17/17	1	NM_001131016.2	P2

Frequencies

GnomAD3 genomes AF: 0.0000561 AC: 8 AN: 142616 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000419

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000226

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000506

GnomAD3 exomes AF: 0.0000323 AC: 5 AN: 154990 Hom.: 0 AF XY: 0.0000124 AC XY: 1 AN XY: 80822

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000824

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000147

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000157

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000151 AC: 20 AN: 1326876 Hom.: 0 Cov.: 33 AF XY: 0.0000108 AC XY: 7 AN XY: 647866

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000594

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000883

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000107

Gnomad4 OTH exome AF: 0.0000560

GnomAD4 genome AF: 0.0000561 AC: 8 AN: 142616 Hom.: 0 Cov.: 31 AF XY: 0.0000289 AC XY: 2 AN XY: 69116

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000419

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000226

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.000506

Alfa AF: 0.0000843 Hom.: 0

Bravo AF: 0.0000982

ExAC AF: 0.0000167 AC: 2

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Dystonic disorder Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jun 29, 2023

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. 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 glutamine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. ClinVar contains an entry for this variant (Variation ID: 2171235). This variant has not been reported in the literature in individuals affected with CIZ1-related conditions. This variant is present in population databases (rs772580580, gnomAD 0.02%). This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 883 of the CIZ1 protein (p.Arg883Gln). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.072
BayesDel_addAF	Benign	-0.53	T
BayesDel_noAF	Benign	-0.74
Cadd	Benign	0.89
Dann	Benign	0.88
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.022	N
LIST_S2	Benign	0.83	T;T;T;T;T;.;T;.;T;T
M_CAP	Benign	0.0080	T
MetaRNN	Benign	0.020	T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	1.0	N;N;N;N;N;N;N;N;N;N
PrimateAI	Benign	0.22	T
PROVEAN	Benign	-0.39	N;.;N;.;.;N;N;N;.;N
REVEL	Benign	0.015
Sift	Benign	0.37	T;.;T;.;.;T;T;T;.;T
Sift4G	Benign	0.70	T;T;T;T;T;T;T;T;T;T
Polyphen		0.043	B;.;B;.;.;B;B;B;B;.
Vest4		0.099
MutPred		0.089		.;.;.;.;.;.;.;Loss of MoRF binding (P = 0.0145);Loss of MoRF binding (P = 0.0145);.;
MVP		0.48
MPC		0.31
ClinPred		0.014	T
GERP RS		-7.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.0094
gMVP		0.17

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

Other links and lift over

dbSNP: rs772580580; hg19: chr9-130928525;