12-119840437-T-C

Variant names:

• chr12-119840437-T-C
• rs4766950
• NM_001206999.2:c.517-6209A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001206999.2(CIT):​c.517-6209A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.432 in 151,966 control chromosomes in the GnomAD database, including 15,279 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.43 (15279 hom., cov: 32)
• Consequence: CIT NM_001206999.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.674
• Publications: 9 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.493 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CIT	NM_001206999.2	c.517-6209A>G		intron_variant	Intron 5 of 47	ENST00000392521.7	NP_001193928.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CIT	ENST00000392521.7	c.517-6209A>G		intron_variant	Intron 5 of 47	1	NM_001206999.2	ENSP00000376306.2
CIT	ENST00000261833.11	c.517-6209A>G		intron_variant	Intron 5 of 46	1		ENSP00000261833.7
CIT	ENST00000536325.1	c.267+9737A>G		intron_variant	Intron 2 of 2	3		ENSP00000443199.1

Frequencies

GnomAD3 genomes AF: 0.432 AC: 65620 AN: 151846 Hom.: 15280 Cov.: 32

Gnomad AFR AF: 0.257

Gnomad AMI AF: 0.426

Gnomad AMR AF: 0.470

Gnomad ASJ AF: 0.604

Gnomad EAS AF: 0.419

Gnomad SAS AF: 0.505

Gnomad FIN AF: 0.548

Gnomad MID AF: 0.522

Gnomad NFE AF: 0.497

Gnomad OTH AF: 0.483

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.432 AC: 65637 AN: 151966 Hom.: 15279 Cov.: 32 AF XY: 0.436 AC XY: 32380 AN XY: 74258

African (AFR) AF: 0.257 AC: 10626 AN: 41424

American (AMR) AF: 0.471 AC: 7196 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.604 AC: 2096 AN: 3468

East Asian (EAS) AF: 0.419 AC: 2163 AN: 5160

South Asian (SAS) AF: 0.504 AC: 2429 AN: 4816

European-Finnish (FIN) AF: 0.548 AC: 5780 AN: 10550

Middle Eastern (MID) AF: 0.520 AC: 153 AN: 294

European-Non Finnish (NFE) AF: 0.497 AC: 33791 AN: 67956

Other (OTH) AF: 0.483 AC: 1017 AN: 2106

Alfa AF: 0.475 Hom.: 59692

Bravo AF: 0.421

Asia WGS AF: 0.464 AC: 1614 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	1.6
DANN	Benign	0.77
PhyloP100		-0.67
Mutation Taster		=100/0	polymorphism (auto)

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: rs4766950; hg19: chr12-120278241;