12-119782478-A-G

Variant names:

• chr12-119782478-A-G
• rs440299
• NM_001206999.2:c.1665+40T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001206999.2(CIT):​c.1665+40T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.468 in 1,602,542 control chromosomes in the GnomAD database, including 177,630 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.45 (15600 hom., cov: 31)
  • Exomes 𝑓: 0.47 (162030 hom.)
• Consequence: CIT NM_001206999.2 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -5.91
• Publications: 7 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.98).
• BP6: Variant 12-119782478-A-G is Benign according to our data. Variant chr12-119782478-A-G is described in ClinVar as Benign. ClinVar VariationId is 1247335.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.551 is higher than 0.05.

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.1665+40T>C		intron	N/A	NP_001193928.1
	CIT	NM_007174.3		c.1665+40T>C		intron	N/A	NP_009105.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CIT	ENST00000392521.7	TSL:1 MANE Select	c.1665+40T>C		intron	N/A	ENSP00000376306.2
	CIT	ENST00000261833.11	TSL:1	c.1665+40T>C		intron	N/A	ENSP00000261833.7
	CIT	ENST00000488203.1	TSL:2	n.1961T>C		non_coding_transcript_exon	Exon 3 of 3

Frequencies

GnomAD3 genomes AF: 0.446 AC: 67614 AN: 151642 Hom.: 15597 Cov.: 31

Gnomad AFR AF: 0.344

Gnomad AMI AF: 0.379

Gnomad AMR AF: 0.561

Gnomad ASJ AF: 0.548

Gnomad EAS AF: 0.404

Gnomad SAS AF: 0.460

Gnomad FIN AF: 0.504

Gnomad MID AF: 0.509

Gnomad NFE AF: 0.469

Gnomad OTH AF: 0.479

GnomAD2 exomes AF: 0.478 AC: 117789 AN: 246292 AF XY: 0.475

Gnomad AFR exome AF: 0.347

Gnomad AMR exome AF: 0.595

Gnomad ASJ exome AF: 0.542

Gnomad EAS exome AF: 0.390

Gnomad FIN exome AF: 0.496

Gnomad NFE exome AF: 0.469

Gnomad OTH exome AF: 0.506

GnomAD4 exome AF: 0.470 AC: 682233 AN: 1450782 Hom.: 162030 Cov.: 30 AF XY: 0.470 AC XY: 339036 AN XY: 721032

African (AFR) AF: 0.349 AC: 11534 AN: 33078

American (AMR) AF: 0.588 AC: 25706 AN: 43684

Ashkenazi Jewish (ASJ) AF: 0.549 AC: 14162 AN: 25804

East Asian (EAS) AF: 0.398 AC: 15744 AN: 39520

South Asian (SAS) AF: 0.460 AC: 39248 AN: 85256

European-Finnish (FIN) AF: 0.500 AC: 26460 AN: 52952

Middle Eastern (MID) AF: 0.523 AC: 2544 AN: 4864

European-Non Finnish (NFE) AF: 0.469 AC: 518480 AN: 1105800

Other (OTH) AF: 0.474 AC: 28355 AN: 59824

GnomAD4 genome AF: 0.446 AC: 67642 AN: 151760 Hom.: 15600 Cov.: 31 AF XY: 0.446 AC XY: 33101 AN XY: 74140

African (AFR) AF: 0.344 AC: 14248 AN: 41378

American (AMR) AF: 0.561 AC: 8554 AN: 15244

Ashkenazi Jewish (ASJ) AF: 0.548 AC: 1899 AN: 3466

East Asian (EAS) AF: 0.404 AC: 2081 AN: 5152

South Asian (SAS) AF: 0.459 AC: 2199 AN: 4790

European-Finnish (FIN) AF: 0.504 AC: 5289 AN: 10498

Middle Eastern (MID) AF: 0.510 AC: 150 AN: 294

European-Non Finnish (NFE) AF: 0.469 AC: 31871 AN: 67914

Other (OTH) AF: 0.476 AC: 1005 AN: 2112

Alfa AF: 0.430 Hom.: 4823

Bravo AF: 0.449

Asia WGS AF: 0.466 AC: 1621 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Jul 06, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.98
CADD	Benign	0.11
DANN	Benign	0.27
PhyloP100		-5.9
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: rs440299; hg19: chr12-120220282; COSMIC: COSV55879870; COSMIC: COSV55879870;