12-119690188-G-T

Position:

• chr12-119690188-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_001206999.2(CIT):​c.6149C>A​(p.Ala2050Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000749 in 1,334,776 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 7.5e-7 (0 hom.)
• Consequence: CIT NM_001206999.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.414

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), CIT. . Gene score misZ 3.8214 (greater than the threshold 3.09). Trascript score misZ 5.1629 (greater than threshold 3.09). GenCC has associacion of gene with microcephaly 11, primary, autosomal recessive, microcephaly 17, primary, autosomal recessive, autosomal recessive primary microcephaly.
• BP4: Computational evidence support a benign effect (MetaRNN=0.07654774).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CIT	NM_001206999.2	c.6149C>A	p.Ala2050Glu	missense_variant	47/48	ENST00000392521.7	NP_001193928.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CIT	ENST00000392521.7	c.6149C>A	p.Ala2050Glu	missense_variant	47/48	1	NM_001206999.2	ENSP00000376306.2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 7.49e-7 AC: 1 AN: 1334776 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 654176

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000248

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 07, 2023

The c.6149C>A (p.A2050E) alteration is located in exon 47 (coding exon 46) of the CIT gene. This alteration results from a C to A substitution at nucleotide position 6149, causing the alanine (A) at amino acid position 2050 to be replaced by a glutamic acid (E). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.28
BayesDel_addAF	Benign	-0.093	T
BayesDel_noAF	Benign	-0.37
CADD	Benign	13
DANN	Benign	0.97
DEOGEN2	Benign	0.18	.;T
Eigen	Benign	-0.88
Eigen_PC	Benign	-0.87
FATHMM_MKL	Benign	0.33	N
LIST_S2	Uncertain	0.95	D;D
M_CAP	Benign	0.019	T
MetaRNN	Benign	0.077	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.34	.;N
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-0.39	N;N
REVEL	Benign	0.10
Sift	Benign	0.060	T;T
Sift4G	Uncertain	0.025	D;D
Polyphen		0.057	.;B
Vest4		0.33
MutPred		0.20		.;Gain of catalytic residue at L2006 (P = 0.0281);
MVP		0.65
MPC		0.81
ClinPred		0.18	T
GERP RS		-1.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.057
gMVP		0.15

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr12-120127993;