rs56212782

Variant names:

• chr12-119688253-G-C
• rs56212782
• NM_001206999.2:c.6189C>G

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP4 BP6_Very_Strong BS1 BS2

The NM_001206999.2(CIT):​c.6189C>G​(p.Val2063Val) variant causes a splice region, synonymous change. The variant allele was found at a frequency of 0.000376 in 1,602,342 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00048 (1 hom., cov: 33)
  • Exomes 𝑓: 0.00037 (2 hom.)
• Consequence: CIT NM_001206999.2 splice_region, synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 3.67
• Publications: 1 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.

• BP4: Computational evidence support a benign effect (REVEL=0.216).
• BP6: Variant 12-119688253-G-C is Benign according to our data. Variant chr12-119688253-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 731244.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.000476 (67/140748) while in subpopulation EAS AF = 0.0118 (61/5176). AF 95% confidence interval is 0.00942. There are 1 homozygotes in GnomAd4. There are 36 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CIT	NM_001206999.2	c.6189C>G	p.Val2063Val	splice_region_variant, synonymous_variant	Exon 48 of 48	ENST00000392521.7	NP_001193928.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CIT	ENST00000392521.7	c.6189C>G	p.Val2063Val	splice_region_variant, synonymous_variant	Exon 48 of 48	1	NM_001206999.2	ENSP00000376306.2

Frequencies

GnomAD3 genomes AF: 0.000476 AC: 67 AN: 140638 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0118

Gnomad SAS AF: 0.000645

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000463

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00107 AC: 265 AN: 248474 AF XY: 0.00111

Gnomad AFR exome AF: 0.0000647

Gnomad AMR exome AF: 0.0000584

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0128

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000891

Gnomad OTH exome AF: 0.000499

GnomAD4 exome AF: 0.000366 AC: 535 AN: 1461594 Hom.: 2 Cov.: 30 AF XY: 0.000384 AC XY: 279 AN XY: 727124

African (AFR) AF: 0.0000299 AC: 1 AN: 33468

American (AMR) AF: 0.0000447 AC: 2 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.0104 AC: 412 AN: 39698

South Asian (SAS) AF: 0.000406 AC: 35 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5768

European-Non Finnish (NFE) AF: 0.0000396 AC: 44 AN: 1111736

Other (OTH) AF: 0.000662 AC: 40 AN: 60392

GnomAD4 genome AF: 0.000476 AC: 67 AN: 140748 Hom.: 1 Cov.: 33 AF XY: 0.000523 AC XY: 36 AN XY: 68794

African (AFR) AF: 0.00 AC: 0 AN: 35118

American (AMR) AF: 0.00 AC: 0 AN: 14430

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3362

East Asian (EAS) AF: 0.0118 AC: 61 AN: 5176

South Asian (SAS) AF: 0.000645 AC: 3 AN: 4652

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10160

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 278

European-Non Finnish (NFE) AF: 0.0000463 AC: 3 AN: 64726

Other (OTH) AF: 0.00 AC: 0 AN: 1956

Alfa AF: 0.000134 Hom.: 0

Bravo AF: 0.000657

Asia WGS AF: 0.00549 AC: 19 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Oct 20, 2019

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 10, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.33
CADD	Benign	13
DANN	Benign	0.87
PhyloP100		3.7
Mutation Taster		=85/15	polymorphism

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: rs56212782; hg19: chr12-120126058;