12-119783832-C-T

Variant names:

• chr12-119783832-C-T
• rs2240310
• NM_001206999.2:c.1545+76G>A

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.1545+76G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.446 in 1,478,510 control chromosomes in the GnomAD database, including 149,683 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.40 (13288 hom., cov: 32)
  • Exomes 𝑓: 0.45 (136395 hom.)
• Consequence: CIT NM_001206999.2 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.74
• Publications: 10 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=-0.67).
• BP6: Variant 12-119783832-C-T is Benign according to our data. Variant chr12-119783832-C-T is described in ClinVar as Benign. ClinVar VariationId is 1179805.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.524 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CIT	NM_001206999.2	c.1545+76G>A		intron_variant	Intron 12 of 47	ENST00000392521.7	NP_001193928.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CIT	ENST00000392521.7	c.1545+76G>A		intron_variant	Intron 12 of 47	1	NM_001206999.2	ENSP00000376306.2

Frequencies

GnomAD3 genomes AF: 0.403 AC: 61235 AN: 151876 Hom.: 13291 Cov.: 32

Gnomad AFR AF: 0.242

Gnomad AMI AF: 0.377

Gnomad AMR AF: 0.533

Gnomad ASJ AF: 0.536

Gnomad EAS AF: 0.399

Gnomad SAS AF: 0.452

Gnomad FIN AF: 0.485

Gnomad MID AF: 0.491

Gnomad NFE AF: 0.448

Gnomad OTH AF: 0.445

GnomAD4 exome AF: 0.451 AC: 598677 AN: 1326516 Hom.: 136395 Cov.: 21 AF XY: 0.452 AC XY: 294257 AN XY: 651274

African (AFR) AF: 0.240 AC: 7071 AN: 29422

American (AMR) AF: 0.564 AC: 16405 AN: 29100

Ashkenazi Jewish (ASJ) AF: 0.539 AC: 10565 AN: 19592

East Asian (EAS) AF: 0.395 AC: 15272 AN: 38636

South Asian (SAS) AF: 0.455 AC: 30974 AN: 68142

European-Finnish (FIN) AF: 0.481 AC: 23739 AN: 49370

Middle Eastern (MID) AF: 0.503 AC: 1823 AN: 3622

European-Non Finnish (NFE) AF: 0.453 AC: 468054 AN: 1033942

Other (OTH) AF: 0.453 AC: 24774 AN: 54690

GnomAD4 genome AF: 0.403 AC: 61240 AN: 151994 Hom.: 13288 Cov.: 32 AF XY: 0.406 AC XY: 30136 AN XY: 74288

African (AFR) AF: 0.242 AC: 10023 AN: 41492

American (AMR) AF: 0.533 AC: 8137 AN: 15254

Ashkenazi Jewish (ASJ) AF: 0.536 AC: 1858 AN: 3466

East Asian (EAS) AF: 0.399 AC: 2058 AN: 5162

South Asian (SAS) AF: 0.451 AC: 2171 AN: 4810

European-Finnish (FIN) AF: 0.485 AC: 5120 AN: 10562

Middle Eastern (MID) AF: 0.497 AC: 146 AN: 294

European-Non Finnish (NFE) AF: 0.448 AC: 30450 AN: 67930

Other (OTH) AF: 0.442 AC: 933 AN: 2112

Alfa AF: 0.435 Hom.: 40601

Bravo AF: 0.403

Asia WGS AF: 0.449 AC: 1562 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

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Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.67
CADD	Benign	21
DANN	Benign	0.79
PhyloP100		1.7
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: rs2240310; hg19: chr12-120221636; COSMIC: COSV55859520; COSMIC: COSV55859520;