rs780188256

Positions:

chr9-128177654-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.1730C>T(p.Ser577Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000149 in 1,593,114 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00014 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00015 ( 0 hom. )

Consequence

CIZ1
NM_001131016.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.55

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]

CIZ1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.08279571).

BS2

High AC in GnomAd4 at 21 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CIZ1	NM_001131016.2 linkuse as main transcript	c.1730C>T	p.Ser577Phe	missense_variant	10/17	ENST00000372938.10	NP_001124488.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CIZ1	ENST00000372938.10 linkuse as main transcript	c.1730C>T	p.Ser577Phe	missense_variant	10/17	1	NM_001131016.2	ENSP00000362029	P2	Q9ULV3-1

Frequencies

GnomAD3 genomes

AF:

0.000138

AC:

AN:

152166

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000262

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000941

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000206

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.0000886

AC:

AN:

214532

Hom.:

AF XY:

0.0000951

AC XY:

AN XY:

115696

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000326

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:

0.000189

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000151

AC:

217

AN:

1440948

Hom.:

Cov.:

AF XY:

0.000143

AC XY:

102

AN XY:

714774

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000145

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.000135

Gnomad4 NFE exome

AF:

0.000179

Gnomad4 OTH exome

AF:

0.000118

GnomAD4 genome

AF:

0.000138

AC:

AN:

152166

Hom.:

Cov.:

AF XY:

0.000161

AC XY:

AN XY:

74322

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.000262

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.0000941

Gnomad4 NFE

AF:

0.000206

Gnomad4 OTH

AF:

0.000478

Alfa

AF:

0.000136

Hom.:

Bravo

AF:

0.0000982

ExAC

AF:

0.0000991

AC:

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 submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Sep 03, 2022

ClinVar contains an entry for this variant (Variation ID: 580942). 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: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C65". The phenylalanine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. This missense change has been observed in individual(s) with autosomal dominant primary cervical dystonia in a family (PMID: 22447717). This variant is present in population databases (rs780188256, gnomAD 0.01%). This sequence change replaces serine, which is neutral and polar, with phenylalanine, which is neutral and non-polar, at codon 577 of the CIZ1 protein (p.Ser577Phe). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.36

BayesDel_noAF

Benign

-0.49

CADD

Benign

DANN

Benign

0.70

DEOGEN2

Benign

0.083

.;.;T;T;.;T;.;T;T;.

Eigen

Benign

-0.83

Eigen_PC

Benign

-0.78

FATHMM_MKL

Benign

0.60

LIST_S2

Benign

0.78

T;T;T;T;T;.;T;.;T;T

M_CAP

Benign

0.0065

MetaRNN

Benign

0.083

T;T;T;T;T;T;T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Uncertain

2.3

.;.;.;.;.;.;.;M;M;.

MutationTaster

Benign

1.0

D;N;N;N;N;N;N;N;N;N

PrimateAI

Benign

0.32

PROVEAN

Benign

-1.9

N;.;N;.;.;N;N;N;.;D

REVEL

Benign

0.11

Sift

Uncertain

0.020

D;.;D;.;.;D;D;D;.;D

Sift4G

Benign

0.12

T;T;T;T;T;T;T;T;T;T

Polyphen

0.033

B;.;B;.;.;B;B;B;B;.

Vest4

0.11

MutPred

0.28

.;.;.;.;.;.;.;Loss of glycosylation at S577 (P = 0.0014);Loss of glycosylation at S577 (P = 0.0014);.;

MVP

0.22

MPC

0.30

ClinPred

0.066

GERP RS

3.8

Varity_R

0.064

gMVP

0.21

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.070

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over