Genetic Variant CIT:p.Ala2050Val (chr12-119690188-G-A) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001206999.2(CIT):c.6149C>T(p.Ala2050Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000045 in 1,334,770 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A2050E) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 0.0000045 ( 0 hom. )

Consequence

CIT
NM_001206999.2 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.414

Publications

3 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: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.043729395).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CIT	NM_001206999.2 link	c.6149C>T	p.Ala2050Val	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.6149C>T	p.Ala2050Val	missense_variant	Exon 47 of 48	1	NM_001206999.2	ENSP00000376306.2		O14578-4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000450

AC:

AN:

1334770

Hom.:

Cov.:

AF XY:

0.00000459

AC XY:

AN XY:

654176

show subpopulations

African (AFR)

AF:

0.0000360

AC:

AN:

27814

American (AMR)

AF:

0.00

AC:

AN:

25790

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19972

East Asian (EAS)

AF:

0.00

AC:

AN:

35226

South Asian (SAS)

AF:

0.00

AC:

AN:

65110

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40284

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5276

European-Non Finnish (NFE)

AF:

0.00000472

AC:

AN:

1060044

Other (OTH)

AF:

0.00

AC:

AN:

55254

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.062

BayesDel_addAF

Benign

-0.15

BayesDel_noAF

Benign

-0.46

CADD

Benign

6.0

(source)

DANN

Benign

0.59

DEOGEN2

Benign

0.16

.;T

Eigen

Benign

-0.73

Eigen_PC

Benign

-0.77

FATHMM_MKL

Benign

0.027

LIST_S2

Uncertain

0.89

D;D

M_CAP

Benign

0.010

MetaRNN

Benign

0.044

T;T

MetaSVM

Benign

-0.99

MutationAssessor

Benign

0.34

.;N

PhyloP100

0.41

PrimateAI

Benign

0.34

PROVEAN

Benign

-0.16

N;N

REVEL

Benign

0.10

Sift

Benign

0.51

T;T

Sift4G

Benign

0.55

T;T

Polyphen

0.0

.;B

Vest4

0.15

MutPred

0.16

.;Gain of catalytic residue at L2006 (P = 0.0208);

MVP

0.52

MPC

0.63

ClinPred

0.19

GERP RS

-1.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.017

gMVP

0.061

Mutation Taster

=97/3

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

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12-119690188-G-A

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over