rs749796555

Variant names:

• chr12-119690167-A-G
• rs749796555
• NM_001206999.2:c.6170T>C

Your query was ambiguous. Multiple possible variants found:

• chr12-119690167-A-G
• chr12-119690167-A-T

Variant summary

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

The NM_001206999.2(CIT):​c.6170T>C​(p.Leu2057Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000196 in 1,478,992 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: 0.000021 (0 hom.)
• Consequence: CIT NM_001206999.2 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 8.32
• 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.6170T>C	p.Leu2057Pro	missense	Exon 47 of 48	NP_001193928.1	O14578-4
	CIT	NM_007174.3		c.6044T>C	p.Leu2015Pro	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.6170T>C	p.Leu2057Pro	missense	Exon 47 of 48	ENSP00000376306.2	O14578-4
	CIT	ENST00000261833.11	TSL:1	c.6044T>C	p.Leu2015Pro	missense	Exon 46 of 47	ENSP00000261833.7	O14578-1
	CIT	ENST00000928243.1		c.6167T>C	p.Leu2056Pro	missense	Exon 47 of 48	ENSP00000598302.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152194 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000216 AC: 3 AN: 139178 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000619

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000277

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000211 AC: 28 AN: 1326798 Hom.: 0 Cov.: 31 AF XY: 0.0000231 AC XY: 15 AN XY: 648528

African (AFR) AF: 0.00 AC: 0 AN: 27786

American (AMR) AF: 0.0000396 AC: 1 AN: 25256

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19310

East Asian (EAS) AF: 0.00 AC: 0 AN: 35124

South Asian (SAS) AF: 0.00 AC: 0 AN: 63294

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40800

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5242

European-Non Finnish (NFE) AF: 0.0000256 AC: 27 AN: 1054980

Other (OTH) AF: 0.00 AC: 0 AN: 55006

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152194 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 74356

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 41460

American (AMR) AF: 0.00 AC: 0 AN: 15276

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10628

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

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68022

Other (OTH) AF: 0.00 AC: 0 AN: 2092

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.0000113

ExAC AF: 0.00000846 AC: 1

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.31
BayesDel_addAF	Uncertain	0.021	T
BayesDel_noAF	Uncertain	-0.030
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.32	T
Eigen	Uncertain	0.66
Eigen_PC	Pathogenic	0.68
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.96	D
M_CAP	Uncertain	0.11	D
MetaRNN	Uncertain	0.69	D
MetaSVM	Uncertain	-0.14	T
MutationAssessor	Benign	0.69	N
PhyloP100		8.3
PrimateAI	Pathogenic	0.80	T
PROVEAN	Benign	-1.1	N
REVEL	Uncertain	0.32
Sift	Uncertain	0.0020	D
Sift4G	Pathogenic	0.0010	D
Polyphen		0.99	D
Vest4		0.95
MutPred		0.27		Gain of catalytic residue at P2014 (P = 0.0028)
MVP		0.81
MPC		1.9
ClinPred		0.42	T
GERP RS		5.4
Varity_R		0.40
gMVP		0.51
Mutation Taster		=54/46	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: rs749796555; hg19: chr12-120127972;