12-119690338-C-T

Variant names:

• chr12-119690338-C-T
• rs200787337
• NM_001206999.2:c.5999G>A

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
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 7.73
• Publications: 2 publications found

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: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• autosomal recessive primary microcephaly

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001206999.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CIT	NM_001206999.2	MANE Select	c.5999G>A	p.Arg2000His	missense	Exon 47 of 48	NP_001193928.1	O14578-4
	CIT	NM_007174.3		c.5873G>A	p.Arg1958His	missense	Exon 46 of 47	NP_009105.1	O14578-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CIT	ENST00000392521.7	TSL:1 MANE Select	c.5999G>A	p.Arg2000His	missense	Exon 47 of 48	ENSP00000376306.2	O14578-4
	CIT	ENST00000261833.11	TSL:1	c.5873G>A	p.Arg1958His	missense	Exon 46 of 47	ENSP00000261833.7	O14578-1
	CIT	ENST00000928243.1		c.5996G>A	p.Arg1999His	missense	Exon 47 of 48	ENSP00000598302.1

Frequencies

GnomAD3 genomes AF: 0.000177 AC: 27 AN: 152174 Hom.: 0 Cov.: 31

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: 18 AN: 227302 AF XY: 0.0000958

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.: 0 Cov.: 31 AF XY: 0.000158 AC XY: 114 AN XY: 719332

African (AFR) AF: 0.00 AC: 0 AN: 33310

American (AMR) AF: 0.00 AC: 0 AN: 43980

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25950

East Asian (EAS) AF: 0.00 AC: 0 AN: 39484

South Asian (SAS) AF: 0.0000117 AC: 1 AN: 85554

European-Finnish (FIN) AF: 0.000197 AC: 8 AN: 40674

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5750

European-Non Finnish (NFE) AF: 0.000199 AC: 221 AN: 1110244

Other (OTH) AF: 0.000200 AC: 12 AN: 60062

GnomAD4 genome AF: 0.000177 AC: 27 AN: 152292 Hom.: 0 Cov.: 31 AF XY: 0.000228 AC XY: 17 AN XY: 74446

African (AFR) AF: 0.0000481 AC: 2 AN: 41558

American (AMR) AF: 0.00 AC: 0 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5160

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00113 AC: 12 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000191 AC: 13 AN: 68040

Other (OTH) AF: 0.00 AC: 0 AN: 2110

Alfa AF: 0.000101 Hom.: 0

Bravo AF: 0.0000869

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ExAC AF: 0.0000581 AC: 7

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	2	-	not provided (2)
-	1	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.57
BayesDel_addAF	Uncertain	0.031	T
BayesDel_noAF	Uncertain	0.030
CADD	Pathogenic	32
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.28	T
Eigen	Pathogenic	0.83
Eigen_PC	Pathogenic	0.82
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Benign	0.049	D
MetaRNN	Uncertain	0.49	T
MetaSVM	Uncertain	0.13	D
MutationAssessor	Benign	0.97	L
PhyloP100		7.7
PrimateAI	Pathogenic	0.90	D
PROVEAN	Benign	-0.96	N
REVEL	Uncertain	0.37
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	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	T
GERP RS		5.5
Varity_R		0.42
gMVP		0.38
Mutation Taster		=63/37	polymorphism

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

Other links and lift over

dbSNP: rs200787337; hg19: chr12-120128143;