rs1391138416

Variant names:

• chr9-128180494-T-C
• rs1391138416
• NM_001131016.2:c.712A>G

Your query was ambiguous. Multiple possible variants found:

• chr9-128180494-T-C
• chr9-128180494-T-A

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_001131016.2(CIZ1):​c.712A>G​(p.Ile238Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000136 in 1,614,026 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000014 (0 hom.)
• Consequence: CIZ1 NM_001131016.2 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: -0.860
• 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: Benign. The variant received -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.039842755).
• BS2: High AC in GnomAdExome4 at 20 AD,Unknown gene.

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.712A>G	p.Ile238Val	missense	Exon 7 of 17	NP_001124488.1	Q9ULV3-1
	CIZ1	NM_001257975.2		c.802A>G	p.Ile268Val	missense	Exon 7 of 18	NP_001244904.1	F5H2X7
	CIZ1	NM_012127.3		c.712A>G	p.Ile238Val	missense	Exon 7 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.712A>G	p.Ile238Val	missense	Exon 7 of 17	ENSP00000362029.5	Q9ULV3-1
	CIZ1	ENST00000415526.5	TSL:1	c.478A>G	p.Ile160Val	missense	Exon 5 of 15	ENSP00000398011.1	H0Y5D5
	CIZ1	ENST00000372954.5	TSL:1	c.640A>G	p.Ile214Val	missense	Exon 6 of 17	ENSP00000362045.1	Q9ULV3-3

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152156 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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 AF: 0.0000137 AC: 20 AN: 1461870 Hom.: 0 Cov.: 31 AF XY: 0.0000151 AC XY: 11 AN XY: 727242

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.0000162 AC: 18 AN: 1111996

Other (OTH) AF: 0.0000331 AC: 2 AN: 60396

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152156 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74322

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0000241 AC: 1 AN: 41438

American (AMR) AF: 0.00 AC: 0 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4816

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

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

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68024

Other (OTH) AF: 0.00 AC: 0 AN: 2092

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.0296732), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000227

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Dystonic disorder (1)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.072
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.68
CADD	Benign	0.064
DANN	Benign	0.25
DEOGEN2	Benign	0.0083	T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.084	N
LIST_S2	Benign	0.66	T
M_CAP	Benign	0.0045	T
MetaRNN	Benign	0.040	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.14	N
PhyloP100		-0.86
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-0.16	N
REVEL	Benign	0.0030
Sift	Benign	0.14	T
Sift4G	Benign	1.0	T
Polyphen		0.0020	B
Vest4		0.086
MutPred		0.16		Loss of glycosylation at K242 (P = 0.1781)
MVP		0.19
MPC		0.22
ClinPred		0.029	T
GERP RS		-2.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.018
gMVP		0.028
Mutation Taster		=94/6	polymorphism

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

Other links and lift over

dbSNP: rs1391138416; hg19: chr9-130942773;