12-119714279-G-A

Variant names:

• chr12-119714279-G-A
• rs34105832
• NM_001206999.2:c.4224C>T

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP6_Very_Strong BP7 BS1 BS2

The NM_001206999.2(CIT):​c.4224C>T​(p.Asn1408Asn) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00826 in 1,614,092 control chromosomes in the GnomAD database, including 71 homozygotes. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0054 (2 hom., cov: 33)
  • Exomes 𝑓: 0.0085 (69 hom.)
• Consequence: CIT NM_001206999.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.906
• Publications: 3 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 -17 ACMG points.

• BP6: Variant 12-119714279-G-A is Benign according to our data. Variant chr12-119714279-G-A is described in ClinVar as Benign. ClinVar VariationId is 434770.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.906 with no splicing effect.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00545 (829/152226) while in subpopulation SAS AF = 0.0108 (52/4818). AF 95% confidence interval is 0.00868. There are 2 homozygotes in GnomAd4. There are 357 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 2 AR gene

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CIT	NM_001206999.2	MANE Select	c.4224C>T	p.Asn1408Asn	synonymous	Exon 33 of 48	NP_001193928.1
	CIT	NM_007174.3		c.4098C>T	p.Asn1366Asn	synonymous	Exon 32 of 47	NP_009105.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CIT	ENST00000392521.7	TSL:1 MANE Select	c.4224C>T	p.Asn1408Asn	synonymous	Exon 33 of 48	ENSP00000376306.2
	CIT	ENST00000261833.11	TSL:1	c.4098C>T	p.Asn1366Asn	synonymous	Exon 32 of 47	ENSP00000261833.7
	CIT	ENST00000928243.1		c.4224C>T	p.Asn1408Asn	synonymous	Exon 33 of 48	ENSP00000598302.1

Frequencies

GnomAD3 genomes AF: 0.00543 AC: 826 AN: 152108 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.00147

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00380

Gnomad ASJ AF: 0.00230

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0102

Gnomad FIN AF: 0.00113

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00928

Gnomad OTH AF: 0.00287

GnomAD2 exomes AF: 0.00649 AC: 1631 AN: 251460 AF XY: 0.00692

Gnomad AFR exome AF: 0.00111

Gnomad AMR exome AF: 0.00405

Gnomad ASJ exome AF: 0.00218

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00162

Gnomad NFE exome AF: 0.00928

Gnomad OTH exome AF: 0.00684

GnomAD4 exome AF: 0.00855 AC: 12496 AN: 1461866 Hom.: 69 Cov.: 31 AF XY: 0.00858 AC XY: 6241 AN XY: 727230

African (AFR) AF: 0.00125 AC: 42 AN: 33480

American (AMR) AF: 0.00414 AC: 185 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00187 AC: 49 AN: 26136

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39700

South Asian (SAS) AF: 0.0108 AC: 933 AN: 86256

European-Finnish (FIN) AF: 0.00225 AC: 120 AN: 53420

Middle Eastern (MID) AF: 0.00433 AC: 25 AN: 5768

European-Non Finnish (NFE) AF: 0.00960 AC: 10672 AN: 1111986

Other (OTH) AF: 0.00775 AC: 468 AN: 60396

GnomAD4 genome AF: 0.00545 AC: 829 AN: 152226 Hom.: 2 Cov.: 33 AF XY: 0.00480 AC XY: 357 AN XY: 74434

African (AFR) AF: 0.00147 AC: 61 AN: 41546

American (AMR) AF: 0.00379 AC: 58 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00230 AC: 8 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5172

South Asian (SAS) AF: 0.0108 AC: 52 AN: 4818

European-Finnish (FIN) AF: 0.00113 AC: 12 AN: 10604

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00928 AC: 631 AN: 68004

Other (OTH) AF: 0.00284 AC: 6 AN: 2110

Alfa AF: 0.00737 Hom.: 0

Bravo AF: 0.00551

Asia WGS AF: 0.00289 AC: 10 AN: 3478

EpiCase AF: 0.00954

EpiControl AF: 0.00699

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.68
CADD	Benign	13
DANN	Benign	0.87
PhyloP100		-0.91
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=99/1	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.10		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: rs34105832; hg19: chr12-120152084; COSMIC: COSV99951291; COSMIC: COSV99951291;