12-119690200-C-A

Variant names:

• chr12-119690200-C-A
• rs779935583
• NM_001206999.2:c.6137G>T

Variant summary

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

The NM_001206999.2(CIT):​c.6137G>T​(p.Gly2046Val) variant causes a missense change. The variant allele was found at a frequency of 0.00000134 in 1,497,314 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 31)
  • Exomes 𝑓: 7.4e-7 (0 hom.)
• Consequence: CIT NM_001206999.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.25
• Publications: 1 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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.6137G>T	p.Gly2046Val	missense	Exon 47 of 48	NP_001193928.1	O14578-4
	CIT	NM_007174.3		c.6011G>T	p.Gly2004Val	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.6137G>T	p.Gly2046Val	missense	Exon 47 of 48	ENSP00000376306.2	O14578-4
	CIT	ENST00000261833.11	TSL:1	c.6011G>T	p.Gly2004Val	missense	Exon 46 of 47	ENSP00000261833.7	O14578-1
	CIT	ENST00000928243.1		c.6134G>T	p.Gly2045Val	missense	Exon 47 of 48	ENSP00000598302.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152196 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000241

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: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000658 AC: 1 AN: 152014 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000585

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 7.43e-7 AC: 1 AN: 1345118 Hom.: 0 Cov.: 31 AF XY: 0.00000151 AC XY: 1 AN XY: 660758

African (AFR) AF: 0.00 AC: 0 AN: 27994

American (AMR) AF: 0.0000377 AC: 1 AN: 26558

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 20740

East Asian (EAS) AF: 0.00 AC: 0 AN: 35424

South Asian (SAS) AF: 0.00 AC: 0 AN: 67582

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40608

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5318

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1065178

Other (OTH) AF: 0.00 AC: 0 AN: 55716

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152196 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 74346

African (AFR) AF: 0.0000241 AC: 1 AN: 41460

American (AMR) AF: 0.00 AC: 0 AN: 15286

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5170

South Asian (SAS) AF: 0.00 AC: 0 AN: 4836

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68026

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.0000151

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Uncertain	0.068	T
BayesDel_noAF	Benign	-0.14
CADD	Uncertain	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.29	T
Eigen	Benign	0.17
Eigen_PC	Uncertain	0.33
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.92	D
M_CAP	Benign	0.021	T
MetaRNN	Uncertain	0.50	D
MetaSVM	Benign	-0.77	T
MutationAssessor	Benign	0.69	N
PhyloP100		5.3
PrimateAI	Uncertain	0.71	T
PROVEAN	Benign	-1.2	N
REVEL	Benign	0.18
Sift	Uncertain	0.014	D
Sift4G	Uncertain	0.027	D
Polyphen		0.28	B
Vest4		0.77
MutPred		0.23		Loss of methylation at R2003 (P = 0.0642)
MVP		0.77
MPC		0.90
ClinPred		0.62	D
GERP RS		5.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.23
gMVP		0.19
Mutation Taster		=93/7	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: rs779935583; hg19: chr12-120128005;