NM_001131016.2:c.1730C>T

Variant names:

• chr9-128177654-G-A
• rs780188256
• NM_001131016.2:c.1730C>T

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Moderate BS2

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
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.55

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 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 rank	MANE	Protein	UniProt
CIZ1	NM_001131016.2	c.1730C>T	p.Ser577Phe	missense_variant	Exon 10 of 17	ENST00000372938.10	NP_001124488.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CIZ1	ENST00000372938.10	c.1730C>T	p.Ser577Phe	missense_variant	Exon 10 of 17	1	NM_001131016.2	ENSP00000362029.5

Frequencies

GnomAD3 genomes AF: 0.000138 AC: 21 AN: 152166 Hom.: 0 Cov.: 32

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: 19 AN: 214532 Hom.: 0 AF XY: 0.0000951 AC XY: 11 AN XY: 115696

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.: 0 Cov.: 34 AF XY: 0.000143 AC XY: 102 AN XY: 714774

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: 21 AN: 152166 Hom.: 0 Cov.: 32 AF XY: 0.000161 AC XY: 12 AN XY: 74322

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.: 0

Bravo AF: 0.0000982

ExAC AF: 0.0000991 AC: 12

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Dystonic disorder Uncertain:1

Jan 06, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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). This variant is present in population databases (rs780188256, gnomAD 0.01%). This missense change has been observed in individual(s) with autosomal dominant primary cervical dystonia in a family (PMID: 22447717). ClinVar contains an entry for this variant (Variation ID: 580942). An algorithm developed to predict the effect of missense changes on protein structure and function outputs the following: PolyPhen-2: "Benign". The phenylalanine 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	-0.36	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	16
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	D
LIST_S2	Benign	0.78	T;T;T;T;T;.;T;.;T;T
M_CAP	Benign	0.0065	T
MetaRNN	Benign	0.083	T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.3	.;.;.;.;.;.;.;M;M;.
PrimateAI	Benign	0.32	T
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	T
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

Other links and lift over

dbSNP: rs780188256; hg19: chr9-130939933;