Genetic Variant CIZ1:p.Arg653Arg (chr9-128170094-T-G) – ACMG Classification: Benign (-21 pts)

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_001131016.2(CIZ1):c.1957A>C(p.Arg653Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0215 in 1,605,114 control chromosomes in the GnomAD database, including 462 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.020 ( 36 hom., cov: 33)

Exomes 𝑓: 0.022 ( 426 hom. )

Consequence

CIZ1
NM_001131016.2 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 1.16

Publications

4 publications found

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 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

CIZ1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.72).

BP6

Variant 9-128170094-T-G is Benign according to our data. Variant chr9-128170094-T-G is described in ClinVar as Benign. ClinVar VariationId is 413832.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=1.16 with no splicing effect.

BS1

Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.02 (2870/143754) while in subpopulation AMR AF = 0.0286 (381/13318). AF 95% confidence interval is 0.0264. There are 36 homozygotes in GnomAd4. There are 1373 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High AC in GnomAd4 at 2870 AD,Unknown gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CIZ1	NM_001131016.2 link	c.1957A>C	p.Arg653Arg	synonymous_variant	Exon 12 of 17	ENST00000372938.10	NP_001124488.1	Q9ULV3-1A0A024R885

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CIZ1	ENST00000372938.10 link	c.1957A>C	p.Arg653Arg	synonymous_variant	Exon 12 of 17	1	NM_001131016.2	ENSP00000362029.5		Q9ULV3-1

Frequencies

GnomAD3 genomes

AF:

0.0200

AC:

2871

AN:

143632

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00436

Gnomad AMI

AF:

0.161

Gnomad AMR

AF:

0.0287

Gnomad ASJ

AF:

0.0379

Gnomad EAS

AF:

0.000203

Gnomad SAS

AF:

0.0131

Gnomad FIN

AF:

0.0162

Gnomad MID

AF:

0.0762

Gnomad NFE

AF:

0.0275

Gnomad OTH

AF:

0.0279

GnomAD2 exomes

AF:

0.0189

AC:

4677

AN:

248022

AF XY:

0.0196

show subpopulations

Gnomad AFR exome

AF:

0.00388

Gnomad AMR exome

AF:

0.0166

Gnomad ASJ exome

AF:

0.0360

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0139

Gnomad NFE exome

AF:

0.0259

Gnomad OTH exome

AF:

0.0253

GnomAD4 exome

AF:

0.0216

AC:

31592

AN:

1461360

Hom.:

426

Cov.:

AF XY:

0.0217

AC XY:

15746

AN XY:

727022

show subpopulations

African (AFR)

AF:

0.00454

AC:

152

AN:

33464

American (AMR)

AF:

0.0164

AC:

729

AN:

44556

Ashkenazi Jewish (ASJ)

AF:

0.0365

AC:

954

AN:

26128

East Asian (EAS)

AF:

0.0000504

AC:

AN:

39698

South Asian (SAS)

AF:

0.0111

AC:

959

AN:

86240

European-Finnish (FIN)

AF:

0.0145

AC:

774

AN:

53416

Middle Eastern (MID)

AF:

0.0526

AC:

303

AN:

5764

European-Non Finnish (NFE)

AF:

0.0237

AC:

26355

AN:

1111718

Other (OTH)

AF:

0.0226

AC:

1364

AN:

60376

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.467

Heterozygous variant carriers

1442

2884

4325

5767

7209

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

940

1880

2820

3760

4700

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0200

AC:

2870

AN:

143754

Hom.:

Cov.:

AF XY:

0.0197

AC XY:

1373

AN XY:

69638

show subpopulations

African (AFR)

AF:

0.00435

AC:

179

AN:

41190

American (AMR)

AF:

0.0286

AC:

381

AN:

13318

Ashkenazi Jewish (ASJ)

AF:

0.0379

AC:

127

AN:

3348

East Asian (EAS)

AF:

0.000203

AC:

AN:

4916

South Asian (SAS)

AF:

0.0129

AC:

AN:

4186

European-Finnish (FIN)

AF:

0.0162

AC:

157

AN:

9710

Middle Eastern (MID)

AF:

0.0775

AC:

AN:

284

European-Non Finnish (NFE)

AF:

0.0275

AC:

1759

AN:

64032

Other (OTH)

AF:

0.0281

AC:

AN:

1924

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

154

308

461

615

769

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

128

160

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0229

Hom.:

Bravo

AF:

0.0191

Asia WGS

AF:

0.00549

AC:

AN:

3478

EpiCase

AF:

0.0309

EpiControl

AF:

0.0303

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Dystonic disorder

Benign:1

Jan 28, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.72

CADD

Benign

9.3

(source)

DANN

Benign

0.64

PhyloP100

1.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over