12-119690338-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP2

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

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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, CIT

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CIT	NM_001206999.2	c.5999G>A	p.Arg2000His	missense_variant	47/48	ENST00000392521.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CIT	ENST00000392521.7	c.5999G>A	p.Arg2000His	missense_variant	47/48	1	NM_001206999.2	P1

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

GnomAD3 exomes AF: 0.0000792 AC: 18 AN: 227302 Hom.: 0 AF XY: 0.0000958 AC XY: 12 AN XY: 125218

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 SAS 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

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: 0.0000117

Gnomad4 FIN exome AF: 0.000197

Gnomad4 NFE exome AF: 0.000199

Gnomad4 OTH exome AF: 0.000200

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

Gnomad4 AFR AF: 0.0000481

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00113

Gnomad4 NFE AF: 0.000191

Gnomad4 OTH AF: 0.00

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

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jul 21, 2021	In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Oct 13, 2022	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 2000 of the CIT protein (p.Arg2000His). This variant is present in population databases (rs200787337, gnomAD 0.04%). This variant has not been reported in the literature in individuals affected with CIT-related conditions. ClinVar contains an entry for this variant (Variation ID: 1254402). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 25, 2022

The c.5999G>A (p.R2000H) alteration is located in exon 47 (coding exon 46) of the CIT gene. This alteration results from a G to A substitution at nucleotide position 5999, causing the arginine (R) at amino acid position 2000 to be replaced by a histidine (H). 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	Pathogenic	0.57
BayesDel_addAF	Uncertain	0.031	T
BayesDel_noAF	Uncertain	0.030
Cadd	Pathogenic	32
Dann	Pathogenic	1.0
Eigen	Pathogenic	0.83
Eigen_PC	Pathogenic	0.82
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Pathogenic	0.99	D;D
M_CAP	Benign	0.049	D
MetaRNN	Uncertain	0.49	T;T
MetaSVM	Uncertain	0.13	D
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.90	D
PROVEAN	Benign	-0.96	N;N
REVEL	Uncertain	0.37
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;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

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

LitVar

Other links and lift over

dbSNP: rs200787337; hg19: chr12-120128143;