NM_001131016.2:c.2563G>T

Variant names:

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

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001131016.2(CIZ1):​c.2563G>T​(p.Ala855Ser) variant causes a missense change. The variant allele was found at a frequency of 0.0000132 in 152,058 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A855T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CIZ1 NM_001131016.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.59
• Publications: 1 publications found

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 Gene-Disease associations (from GenCC):

• dystonia 23

  Inheritance: Unknown Classification: MODERATE Submitted by: Genomics England PanelApp
• inherited dystonia

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.20780241).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001131016.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CIZ1	NM_001131016.2	MANE Select	c.2563G>T	p.Ala855Ser	missense	Exon 17 of 17	NP_001124488.1	Q9ULV3-1
	CIZ1	NM_001257975.2		c.2731G>T	p.Ala911Ser	missense	Exon 18 of 18	NP_001244904.1	F5H2X7
	CIZ1	NM_012127.3		c.2563G>T	p.Ala855Ser	missense	Exon 17 of 17	NP_036259.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CIZ1	ENST00000372938.10	TSL:1 MANE Select	c.2563G>T	p.Ala855Ser	missense	Exon 17 of 17	ENSP00000362029.5	Q9ULV3-1
	CIZ1	ENST00000415526.5	TSL:1	c.2329G>T	p.Ala777Ser	missense	Exon 15 of 15	ENSP00000398011.1	H0Y5D5
	CIZ1	ENST00000372954.5	TSL:1	c.2323G>T	p.Ala775Ser	missense	Exon 17 of 17	ENSP00000362045.1	Q9ULV3-3

Frequencies

GnomAD3 genomes AF: 0.0000132 AC: 2 AN: 152058 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1413186 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 698192

African (AFR) AF: 0.00 AC: 0 AN: 32444

American (AMR) AF: 0.00 AC: 0 AN: 37106

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25238

East Asian (EAS) AF: 0.00 AC: 0 AN: 37224

South Asian (SAS) AF: 0.00 AC: 0 AN: 80222

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50284

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5622

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1086490

Other (OTH) AF: 0.00 AC: 0 AN: 58556

GnomAD4 genome AF: 0.0000132 AC: 2 AN: 152058 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74272

African (AFR) AF: 0.00 AC: 0 AN: 41396

American (AMR) AF: 0.0000655 AC: 1 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10598

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68006

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Dystonic disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.41
BayesDel_addAF	Benign	-0.083	T
BayesDel_noAF	Benign	-0.36
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.044	T
Eigen	Uncertain	0.29
Eigen_PC	Benign	0.20
FATHMM_MKL	Benign	0.65	D
LIST_S2	Uncertain	0.90	D
M_CAP	Benign	0.024	T
MetaRNN	Benign	0.21	T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	1.1	L
PhyloP100		3.6
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	-0.87	N
REVEL	Benign	0.087
Sift	Pathogenic	0.0	D
Sift4G	Benign	0.29	T
Polyphen		1.0	D
Vest4		0.43
MVP		0.37
MPC		0.90
ClinPred		0.88	D
GERP RS		4.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.27
gMVP		0.31
Mutation Taster		=96/4	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs755157078; hg19: chr9-130928610;