12-119690188-G-A

Variant names:

• chr12-119690188-G-A
• rs11547118
• NM_001206999.2:c.6149C>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_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
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.414
• Publications: 3 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: 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).

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.6149C>T	p.Ala2050Val	missense	Exon 47 of 48	NP_001193928.1	O14578-4
	CIT	NM_007174.3		c.6023C>T	p.Ala2008Val	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.6149C>T	p.Ala2050Val	missense	Exon 47 of 48	ENSP00000376306.2	O14578-4
	CIT	ENST00000261833.11	TSL:1	c.6023C>T	p.Ala2008Val	missense	Exon 46 of 47	ENSP00000261833.7	O14578-1
	CIT	ENST00000928243.1		c.6146C>T	p.Ala2049Val	missense	Exon 47 of 48	ENSP00000598302.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000450 AC: 6 AN: 1334770 Hom.: 0 Cov.: 31 AF XY: 0.00000459 AC XY: 3 AN XY: 654176

African (AFR) AF: 0.0000360 AC: 1 AN: 27814

American (AMR) AF: 0.00 AC: 0 AN: 25790

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19972

East Asian (EAS) AF: 0.00 AC: 0 AN: 35226

South Asian (SAS) AF: 0.00 AC: 0 AN: 65110

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40284

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5276

European-Non Finnish (NFE) AF: 0.00000472 AC: 5 AN: 1060044

Other (OTH) AF: 0.00 AC: 0 AN: 55254

GnomAD4 genome Cov.: 31

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.062
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	6.0
DANN	Benign	0.59
DEOGEN2	Benign	0.16	T
Eigen	Benign	-0.73
Eigen_PC	Benign	-0.77
FATHMM_MKL	Benign	0.027	N
LIST_S2	Uncertain	0.89	D
M_CAP	Benign	0.010	T
MetaRNN	Benign	0.044	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	0.34	N
PhyloP100		0.41
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-0.16	N
REVEL	Benign	0.10
Sift	Benign	0.51	T
Sift4G	Benign	0.55	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	T
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

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: rs11547118; hg19: chr12-120127993; COSMIC: COSV55879642; COSMIC: COSV55879642;