rs11549260

Positions:

• chr9-128166354-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001131016.2(CIZ1):​c.2540G>A​(p.Arg847Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0227 in 1,561,462 control chromosomes in the GnomAD database, including 480 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.018 (32 hom., cov: 32)
  • Exomes 𝑓: 0.023 (448 hom.)
• Consequence: CIZ1 NM_001131016.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.883

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0023836792).
• BP6: Variant 9-128166354-C-T is Benign according to our data. Variant chr9-128166354-C-T is described in ClinVar as [Benign]. Clinvar id is 413837.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-128166354-C-T is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0184 (2807/152192) while in subpopulation NFE AF= 0.0258 (1754/67996). AF 95% confidence interval is 0.0248. There are 32 homozygotes in gnomad4. There are 1352 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 2807 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CIZ1	NM_001131016.2	c.2540G>A	p.Arg847Gln	missense_variant	17/17	ENST00000372938.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CIZ1	ENST00000372938.10	c.2540G>A	p.Arg847Gln	missense_variant	17/17	1	NM_001131016.2	P2

Frequencies

GnomAD3 genomes AF: 0.0185 AC: 2808 AN: 152074 Hom.: 32 Cov.: 32

Gnomad AFR AF: 0.00430

Gnomad AMI AF: 0.0143

Gnomad AMR AF: 0.0174

Gnomad ASJ AF: 0.0449

Gnomad EAS AF: 0.000386

Gnomad SAS AF: 0.0130

Gnomad FIN AF: 0.0316

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.0258

Gnomad OTH AF: 0.0163

GnomAD3 exomes AF: 0.0200 AC: 3336 AN: 166696 Hom.: 49 AF XY: 0.0200 AC XY: 1769 AN XY: 88452

Gnomad AFR exome AF: 0.00374

Gnomad AMR exome AF: 0.0141

Gnomad ASJ exome AF: 0.0452

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0142

Gnomad FIN exome AF: 0.0270

Gnomad NFE exome AF: 0.0253

Gnomad OTH exome AF: 0.0250

GnomAD4 exome AF: 0.0232 AC: 32695 AN: 1409270 Hom.: 448 Cov.: 33 AF XY: 0.0229 AC XY: 15944 AN XY: 695976

Gnomad4 AFR exome AF: 0.00396

Gnomad4 AMR exome AF: 0.0141

Gnomad4 ASJ exome AF: 0.0472

Gnomad4 EAS exome AF: 0.0000815

Gnomad4 SAS exome AF: 0.0138

Gnomad4 FIN exome AF: 0.0280

Gnomad4 NFE exome AF: 0.0247

Gnomad4 OTH exome AF: 0.0234

GnomAD4 genome AF: 0.0184 AC: 2807 AN: 152192 Hom.: 32 Cov.: 32 AF XY: 0.0182 AC XY: 1352 AN XY: 74420

Gnomad4 AFR AF: 0.00429

Gnomad4 AMR AF: 0.0173

Gnomad4 ASJ AF: 0.0449

Gnomad4 EAS AF: 0.000386

Gnomad4 SAS AF: 0.0131

Gnomad4 FIN AF: 0.0316

Gnomad4 NFE AF: 0.0258

Gnomad4 OTH AF: 0.0161

Alfa AF: 0.0253 Hom.: 132

Bravo AF: 0.0172

TwinsUK AF: 0.0216 AC: 80

ALSPAC AF: 0.0223 AC: 86

ESP6500AA AF: 0.00460 AC: 20

ESP6500EA AF: 0.0243 AC: 207

ExAC AF: 0.0144 AC: 1669

Asia WGS AF: 0.00347 AC: 13 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Dystonic disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 25, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.57	T
BayesDel_noAF	Benign	-0.57
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.015	.;.;T;T;.;T;.;T;T;.
Eigen	Benign	-0.26
Eigen_PC	Benign	-0.18
FATHMM_MKL	Benign	0.45	N
LIST_S2	Uncertain	0.86	D;D;D;D;D;.;D;.;D;D
MetaRNN	Benign	0.0024	T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.69	.;.;.;.;.;.;.;N;N;.
MutationTaster	Benign	1.0	D;N;N;N;N;N;N;N;N;N
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-0.36	N;.;N;.;.;N;N;N;.;N
REVEL	Benign	0.034
Sift	Benign	0.061	T;.;T;.;.;T;T;T;.;T
Sift4G	Uncertain	0.038	D;D;D;D;T;D;D;D;D;D
Polyphen		0.12	B;.;P;.;.;P;P;P;P;.
Vest4		0.057
MPC		0.35
ClinPred		0.021	T
GERP RS		1.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.8
Varity_R		0.032
gMVP		0.51

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: rs11549260; hg19: chr9-130928633; COSMIC: COSV52974302; COSMIC: COSV52974302;