rs278126

Variant names:

• chr12-119697912-G-T
• rs278126
• NM_001206999.2:c.5702+64C>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.5702+64C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.276 in 1,612,242 control chromosomes in the GnomAD database, including 64,707 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.26 (5582 hom., cov: 32)
  • Exomes 𝑓: 0.28 (59125 hom.)
• Consequence: CIT NM_001206999.2 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.185
• 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=-0.82).
• BP6: Variant 12-119697912-G-T is Benign according to our data. Variant chr12-119697912-G-T is described in ClinVar as Benign. ClinVar VariationId is 1286810.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.294 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.5702+64C>A		intron	N/A	NP_001193928.1
	CIT	NM_007174.3		c.5576+64C>A		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.5702+64C>A		intron	N/A	ENSP00000376306.2
	CIT	ENST00000261833.11	TSL:1	c.5576+64C>A		intron	N/A	ENSP00000261833.7
	CIT	ENST00000544872.1	TSL:4	n.198C>A		non_coding_transcript_exon	Exon 1 of 2

Frequencies

GnomAD3 genomes AF: 0.265 AC: 40196 AN: 151912 Hom.: 5577 Cov.: 32

Gnomad AFR AF: 0.273

Gnomad AMI AF: 0.147

Gnomad AMR AF: 0.223

Gnomad ASJ AF: 0.259

Gnomad EAS AF: 0.0119

Gnomad SAS AF: 0.195

Gnomad FIN AF: 0.245

Gnomad MID AF: 0.345

Gnomad NFE AF: 0.297

Gnomad OTH AF: 0.266

GnomAD4 exome AF: 0.278 AC: 405479 AN: 1460212 Hom.: 59125 Cov.: 32 AF XY: 0.277 AC XY: 200851 AN XY: 726306

African (AFR) AF: 0.278 AC: 9297 AN: 33460

American (AMR) AF: 0.171 AC: 7627 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.258 AC: 6736 AN: 26110

East Asian (EAS) AF: 0.0163 AC: 645 AN: 39672

South Asian (SAS) AF: 0.211 AC: 18201 AN: 86234

European-Finnish (FIN) AF: 0.244 AC: 13017 AN: 53396

Middle Eastern (MID) AF: 0.319 AC: 1835 AN: 5760

European-Non Finnish (NFE) AF: 0.299 AC: 332028 AN: 1110526

Other (OTH) AF: 0.267 AC: 16093 AN: 60342

GnomAD4 genome AF: 0.264 AC: 40206 AN: 152030 Hom.: 5582 Cov.: 32 AF XY: 0.258 AC XY: 19179 AN XY: 74316

African (AFR) AF: 0.273 AC: 11321 AN: 41470

American (AMR) AF: 0.223 AC: 3399 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.259 AC: 897 AN: 3464

East Asian (EAS) AF: 0.0120 AC: 62 AN: 5178

South Asian (SAS) AF: 0.195 AC: 939 AN: 4814

European-Finnish (FIN) AF: 0.245 AC: 2595 AN: 10578

Middle Eastern (MID) AF: 0.344 AC: 101 AN: 294

European-Non Finnish (NFE) AF: 0.297 AC: 20205 AN: 67938

Other (OTH) AF: 0.262 AC: 553 AN: 2114

Alfa AF: 0.287 Hom.: 1017

Bravo AF: 0.263

Asia WGS AF: 0.125 AC: 438 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Jul 17, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	0.72
DANN	Benign	0.76
PhyloP100		0.18
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs278126; hg19: chr12-120135717;