12-119840528-C-T

Variant names:

• chr12-119840528-C-T
• rs4766951
• NM_001206999.2:c.517-6300G>A

Variant summary

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

The NM_001206999.2(CIT):​c.517-6300G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.461 in 151,996 control chromosomes in the GnomAD database, including 16,965 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 0.46 (16965 hom., cov: 32)
• Consequence: CIT NM_001206999.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.601
• Publications: 2 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=-0.56).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.549 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CIT	NM_001206999.2	c.517-6300G>A		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.517-6300G>A		intron_variant	Intron 5 of 47	1	NM_001206999.2	ENSP00000376306.2
CIT	ENST00000261833.11	c.517-6300G>A		intron_variant	Intron 5 of 46	1		ENSP00000261833.7
CIT	ENST00000536325.1	c.267+9646G>A		intron_variant	Intron 2 of 2	3		ENSP00000443199.1

Frequencies

GnomAD3 genomes AF: 0.461 AC: 70036 AN: 151878 Hom.: 16946 Cov.: 32

Gnomad AFR AF: 0.309

Gnomad AMI AF: 0.455

Gnomad AMR AF: 0.494

Gnomad ASJ AF: 0.609

Gnomad EAS AF: 0.502

Gnomad SAS AF: 0.567

Gnomad FIN AF: 0.556

Gnomad MID AF: 0.538

Gnomad NFE AF: 0.512

Gnomad OTH AF: 0.506

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

GnomAD4 genome AF: 0.461 AC: 70096 AN: 151996 Hom.: 16965 Cov.: 32 AF XY: 0.466 AC XY: 34632 AN XY: 74290

African (AFR) AF: 0.310 AC: 12844 AN: 41442

American (AMR) AF: 0.494 AC: 7551 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.609 AC: 2114 AN: 3470

East Asian (EAS) AF: 0.502 AC: 2591 AN: 5166

South Asian (SAS) AF: 0.567 AC: 2727 AN: 4812

European-Finnish (FIN) AF: 0.556 AC: 5862 AN: 10542

Middle Eastern (MID) AF: 0.544 AC: 160 AN: 294

European-Non Finnish (NFE) AF: 0.512 AC: 34765 AN: 67960

Other (OTH) AF: 0.506 AC: 1067 AN: 2110

Alfa AF: 0.455 Hom.: 5498

Bravo AF: 0.451

Asia WGS AF: 0.526 AC: 1829 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.56
CADD	Benign	7.3
DANN	Benign	0.68
PhyloP100		-0.60
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: rs4766951; hg19: chr12-120278332;