9-128166331-C-T

Variant names:

• chr9-128166331-C-T
• rs755157078
• NM_001131016.2:c.2563G>A

Variant summary

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

The NM_001131016.2(CIZ1):​c.2563G>A​(p.Ala855Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00000849 in 1,413,186 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: 0.0000085 (0 hom.)
• Consequence: CIZ1 NM_001131016.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.59

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=0.1571882).
• BS2: High AC in GnomAdExome4 at 12 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CIZ1	NM_001131016.2	c.2563G>A	p.Ala855Thr	missense_variant	Exon 17 of 17	ENST00000372938.10	NP_001124488.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CIZ1	ENST00000372938.10	c.2563G>A	p.Ala855Thr	missense_variant	Exon 17 of 17	1	NM_001131016.2	ENSP00000362029.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000233 AC: 4 AN: 171876 Hom.: 0 AF XY: 0.0000438 AC XY: 4 AN XY: 91320

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000384

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000843

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000144

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000849 AC: 12 AN: 1413186 Hom.: 0 Cov.: 33 AF XY: 0.0000100 AC XY: 7 AN XY: 698192

Gnomad4 AFR exome AF: 0.0000308

Gnomad4 AMR exome AF: 0.0000269

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000249

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000736

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ExAC AF: 0.0000170 AC: 2

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Dec 17, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2563G>A (p.A855T) alteration is located in exon 17 (coding exon 16) of the CIZ1 gene. This alteration results from a G to A substitution at nucleotide position 2563, causing the alanine (A) at amino acid position 855 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.70
BayesDel_addAF	Benign	-0.065	T
BayesDel_noAF	Benign	-0.33
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.048	.;.;T;T;.;T;.;T;T;.
Eigen	Uncertain	0.30
Eigen_PC	Benign	0.22
FATHMM_MKL	Benign	0.61	D
LIST_S2	Uncertain	0.92	D;D;D;D;D;.;D;.;D;D
M_CAP	Benign	0.035	D
MetaRNN	Benign	0.16	T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	1.1	.;.;.;.;.;.;.;L;L;.
PrimateAI	Uncertain	0.61	T
PROVEAN	Benign	-1.5	N;.;N;.;.;N;N;N;.;N
REVEL	Benign	0.11
Sift	Pathogenic	0.0	D;.;D;.;.;D;D;D;.;D
Sift4G	Uncertain	0.011	D;D;D;D;D;D;D;D;D;D
Polyphen		1.0	D;.;D;.;.;D;D;D;D;.
Vest4		0.48
MutPred		0.27		.;.;.;.;.;.;.;Loss of helix (P = 0.0072);Loss of helix (P = 0.0072);.;
MVP		0.35
MPC		0.93
ClinPred		0.39	T
GERP RS		4.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.27
gMVP		0.37

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: rs755157078; hg19: chr9-130928610;