12-119690338-C-T

Variant names:

Variant summary

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

The NM_001206999.2(CIT):c.5999G>A(p.Arg2000His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000168 in 1,597,300 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.00018 ( 0 hom., cov: 31)

Exomes 𝑓: 0.00017 ( 0 hom. )

Consequence

CIT
NM_001206999.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: 7.73

Publications

2 publications found

Variant links:

Genes affected

CIT (HGNC:1985): (citron rho-interacting serine/threonine kinase) This gene encodes a serine/threonine-protein kinase that functions in cell division. Together with the kinesin KIF14, this protein localizes to the central spindle and midbody, and functions to promote efficient cytokinesis. This protein is involved in central nervous system development. Polymorphisms in this gene are associated with bipolar disorder and risk for schizophrenia. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Aug 2011]

CIT Gene-Disease associations (from GenCC):

microcephaly 17, primary, autosomal recessive
Inheritance: AR Classification: STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P
autosomal recessive primary microcephaly
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

CIT links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CIT	NM_001206999.2 link	c.5999G>A	p.Arg2000His	missense_variant	Exon 47 of 48	ENST00000392521.7	NP_001193928.1	O14578-4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CIT	ENST00000392521.7 link	c.5999G>A	p.Arg2000His	missense_variant	Exon 47 of 48	1	NM_001206999.2	ENSP00000376306.2		O14578-4

Frequencies

GnomAD3 genomes

AF:

0.000177

AC:

AN:

152174

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

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:

0.00113

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000191

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000792

AC:

AN:

227302

AF XY:

0.0000958

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000417

Gnomad NFE exome

AF:

0.000105

Gnomad OTH exome

AF:

0.000351

GnomAD4 exome

AF:

0.000167

AC:

242

AN:

1445008

Hom.:

Cov.:

AF XY:

0.000158

AC XY:

114

AN XY:

719332

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33310

American (AMR)

AF:

0.00

AC:

AN:

43980

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25950

East Asian (EAS)

AF:

0.00

AC:

AN:

39484

South Asian (SAS)

AF:

0.0000117

AC:

AN:

85554

European-Finnish (FIN)

AF:

0.000197

AC:

AN:

40674

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5750

European-Non Finnish (NFE)

AF:

0.000199

AC:

221

AN:

1110244

Other (OTH)

AF:

0.000200

AC:

AN:

60062

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.489

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.000177

AC:

AN:

152292

Hom.:

Cov.:

AF XY:

0.000228

AC XY:

AN XY:

74446

show subpopulations

African (AFR)

AF:

0.0000481

AC:

AN:

41558

American (AMR)

AF:

0.00

AC:

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5160

South Asian (SAS)

AF:

0.00

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00113

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000191

AC:

AN:

68040

Other (OTH)

AF:

0.00

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.000101

Hom.:

Bravo

AF:

0.0000869

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ExAC

AF:

0.0000581

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:2

Oct 13, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 2000 of the CIT protein (p.Arg2000His). This variant is present in population databases (rs200787337, gnomAD 0.04%). This variant has not been reported in the literature in individuals affected with CIT-related conditions. ClinVar contains an entry for this variant (Variation ID: 1254402). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Jul 21, 2021

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Inborn genetic diseases

Uncertain:1

Oct 25, 2022

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.5999G>A (p.R2000H) alteration is located in exon 47 (coding exon 46) of the CIT gene. This alteration results from a G to A substitution at nucleotide position 5999, causing the arginine (R) at amino acid position 2000 to be replaced by a histidine (H). 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

0.57

BayesDel_addAF

Uncertain

0.031

BayesDel_noAF

Uncertain

0.030

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.28

.;T

Eigen

Pathogenic

0.83

Eigen_PC

Pathogenic

0.82

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Pathogenic

0.99

D;D

M_CAP

Benign

0.049

MetaRNN

Uncertain

0.49

T;T

MetaSVM

Uncertain

0.13

MutationAssessor

Benign

0.97

.;L

PhyloP100

7.7

PrimateAI

Pathogenic

0.90

PROVEAN

Benign

-0.96

N;N

REVEL

Uncertain

0.37

Sift

Pathogenic

0.0

D;D

Sift4G

Pathogenic

0.0

D;D

Polyphen

1.0

.;D

Vest4

0.81

MutPred

0.20

.;Gain of catalytic residue at T1955 (P = 0.037);

MVP

0.84

MPC

1.8

ClinPred

0.32

GERP RS

5.5

Varity_R

0.42

gMVP

0.38

Mutation Taster

=63/37

polymorphism

(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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

12-119690338-C-T

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