9-128166321-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001131016.2(CIZ1):c.2573C>T(p.Ala858Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000141 in 1,416,238 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: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: CIZ1 NM_001131016.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.86

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.16287136).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CIZ1	NM_001131016.2	c.2573C>T	p.Ala858Val	missense_variant	17/17	ENST00000372938.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CIZ1	ENST00000372938.10	c.2573C>T	p.Ala858Val	missense_variant	17/17	1	NM_001131016.2	P2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000113 AC: 2 AN: 177730 Hom.: 0 AF XY: 0.0000211 AC XY: 2 AN XY: 94608

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000148

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: 0.00000141 AC: 2 AN: 1416238 Hom.: 0 Cov.: 33 AF XY: 0.00000143 AC XY: 1 AN XY: 699946

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000267

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000170

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000756

ExAC AF: 0.00000843 AC: 1

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

Apr 17, 2019

This sequence change replaces alanine with valine at codon 858 of the CIZ1 protein (p.Ala858Val). The alanine residue is highly conserved and there is a small physicochemical difference between alanine and valine. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the ExAC database. This variant has not been reported in the literature in individuals with CIZ1-related conditions. 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, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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	Uncertain	0.34
BayesDel_addAF	Benign	-0.058	T
BayesDel_noAF	Benign	-0.32
Cadd	Pathogenic	26
Dann	Pathogenic	1.0
Eigen	Uncertain	0.40
Eigen_PC	Uncertain	0.33
FATHMM_MKL	Uncertain	0.77	D
LIST_S2	Uncertain	0.92	D;D;D;D;D;.;D;.;D;D
M_CAP	Benign	0.044	D
MetaRNN	Benign	0.16	T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.59	T
MutationTaster	Benign	0.84	D;D;D;D;D;D;D;D;D;D
PrimateAI	Uncertain	0.64	T
PROVEAN	Benign	-1.5	N;.;N;.;.;N;N;N;.;N
REVEL	Benign	0.15
Sift	Pathogenic	0.0	D;.;D;.;.;D;D;D;.;D
Sift4G	Uncertain	0.031	D;D;D;D;D;D;D;D;D;D
Polyphen		1.0	D;.;D;.;.;D;D;D;D;.
Vest4		0.44
MutPred		0.36		.;.;.;.;.;.;.;Gain of sheet (P = 0.0036);Gain of sheet (P = 0.0036);.;
MVP		0.32
MPC		0.94
ClinPred		0.49	T
GERP RS		4.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.33
gMVP		0.33

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: rs766419405; hg19: chr9-130928600;