chr12-119803378-AG-A

Variant names:

• chr12-119803378-AG-A
• rs1057520205
• NM_001206999.2:c.1122delC

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PVS1 PM2

The NM_001206999.2(CIT):​c.1122delC​(p.Phe375SerfsTer30) variant causes a frameshift change. The variant allele was found at a frequency of 0.00000283 in 1,414,570 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000028 (0 hom.)
• Consequence: CIT NM_001206999.2 frameshift
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.76
• Publications: 0 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: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P
• autosomal recessive primary microcephaly

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 10 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CIT	NM_001206999.2	MANE Select	c.1122delC	p.Phe375SerfsTer30	frameshift	Exon 10 of 48	NP_001193928.1
	CIT	NM_007174.3		c.1122delC	p.Phe375SerfsTer30	frameshift	Exon 10 of 47	NP_009105.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CIT	ENST00000392521.7	TSL:1 MANE Select	c.1122delC	p.Phe375SerfsTer30	frameshift	Exon 10 of 48	ENSP00000376306.2
	CIT	ENST00000261833.11	TSL:1	c.1122delC	p.Phe375SerfsTer30	frameshift	Exon 10 of 47	ENSP00000261833.7
	CIT	ENST00000392520.2	TSL:5	c.3delC	p.Phe2LeufsTer8	frameshift	Exon 1 of 38	ENSP00000376305.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000283 AC: 4 AN: 1414570 Hom.: 0 Cov.: 31 AF XY: 0.00000427 AC XY: 3 AN XY: 702210

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

African (AFR) AF: 0.00 AC: 0 AN: 30168

American (AMR) AF: 0.00 AC: 0 AN: 34614

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23446

East Asian (EAS) AF: 0.00 AC: 0 AN: 37432

South Asian (SAS) AF: 0.00 AC: 0 AN: 80082

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5268

European-Non Finnish (NFE) AF: 0.00000366 AC: 4 AN: 1093044

Other (OTH) AF: 0.00 AC: 0 AN: 58098

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0986979), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		3.8

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1057520205; hg19: chr12-120241182;