Genetic Variant CIT:p.Arg2034Gly (chr12-119690237-G-C) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001206999.2(CIT):c.6100C>G(p.Arg2034Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000215 in 1,395,226 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. R2034W) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 0.0000022 ( 0 hom. )

Consequence

CIT
NM_001206999.2 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 3.43

Publications

0 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:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CIT	NM_001206999.2 link	c.6100C>G	p.Arg2034Gly	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.6100C>G	p.Arg2034Gly	missense_variant	Exon 47 of 48	1	NM_001206999.2	ENSP00000376306.2		O14578-4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000215

AC:

AN:

1395226

Hom.:

Cov.:

AF XY:

0.00000145

AC XY:

AN XY:

692002

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

29976

American (AMR)

AF:

0.00

AC:

AN:

31980

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

23662

East Asian (EAS)

AF:

0.00

AC:

AN:

37280

South Asian (SAS)

AF:

0.00

AC:

AN:

78348

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40340

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5542

European-Non Finnish (NFE)

AF:

0.00000275

AC:

AN:

1090188

Other (OTH)

AF:

0.00

AC:

AN:

57910

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.64

BayesDel_addAF

Uncertain

0.14

BayesDel_noAF

Uncertain

-0.030

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.33

.;T

Eigen

Uncertain

0.32

Eigen_PC

Uncertain

0.40

FATHMM_MKL

Uncertain

0.89

LIST_S2

Uncertain

0.95

D;D

M_CAP

Benign

0.053

MetaRNN

Uncertain

0.52

D;D

MetaSVM

Benign

-0.77

MutationAssessor

Benign

0.55

.;N

PhyloP100

3.4

PrimateAI

Uncertain

0.79

PROVEAN

Benign

-1.6

N;N

REVEL

Uncertain

0.30

Sift

Pathogenic

0.0

D;D

Sift4G

Uncertain

0.028

D;D

Polyphen

0.66

.;P

Vest4

0.69

MutPred

0.20

.;Loss of solvent accessibility (P = 0.0159);

MVP

0.88

MPC

1.8

ClinPred

0.68

GERP RS

4.5

Varity_R

0.53

gMVP

0.51

Mutation Taster

=79/21

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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chr12-119690237-G-C

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