NM_001386298.1:c.6280G>C

Variant names:

• chr19-42293039-G-C
• rs587778202
• NM_001386298.1:c.6280G>C

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001386298.1(CIC):​c.6280G>C​(p.Ala2094Pro) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A2094T) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: CIC NM_001386298.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.49
• Publications: 0 publications found

Genes affected

CIC (HGNC:14214): (capicua transcriptional repressor) The protein encoded by this gene is an ortholog of the Drosophila melanogaster capicua gene, and is a member of the high mobility group (HMG)-box superfamily of transcriptional repressors. This protein contains a conserved HMG domain that is involved in DNA binding and nuclear localization, and a conserved C-terminus. Studies suggest that the N-terminal region of this protein interacts with Atxn1 (GeneID:6310), to form a transcription repressor complex, and in vitro studies suggest that polyglutamine-expansion of ATXN1 may alter the repressor activity of this complex. Mutations in this gene have been associated with olidogdendrogliomas (PMID:21817013). In addition, translocation events resulting in gene fusions of this gene with both DUX4 (GeneID:100288687) and FOXO4 (GeneID:4303) have been associated with round cell sarcomas. There are multiple pseudogenes of this gene found on chromosomes 1, 4, 6, 7, 16, 20, and the Y chromosome. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Feb 2015]

CIC Gene-Disease associations (from GenCC):

• intellectual disability, autosomal dominant 45

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Illumina, Labcorp Genetics (formerly Invitae), G2P
• cerebral folate deficiency

  Inheritance: AD Classification: STRONG Submitted by: Franklin by Genoox
• autosomal dominant non-syndromic intellectual disability

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001386298.1. 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
	CIC	NM_001386298.1	MANE Select	c.6280G>C	p.Ala2094Pro	missense	Exon 16 of 21	NP_001373227.1
	CIC	NM_001304815.2		c.6280G>C	p.Ala2094Pro	missense	Exon 16 of 21	NP_001291744.1
	CIC	NM_001379480.1		c.6277G>C	p.Ala2093Pro	missense	Exon 16 of 21	NP_001366409.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CIC	ENST00000681038.1	MANE Select	c.6280G>C	p.Ala2094Pro	missense	Exon 16 of 21	ENSP00000505728.1
	CIC	ENST00000575354.6	TSL:1	c.3553G>C	p.Ala1185Pro	missense	Exon 15 of 20	ENSP00000458663.2
	CIC	ENST00000572681.6	TSL:5	c.6274G>C	p.Ala2092Pro	missense	Exon 16 of 21	ENSP00000459719.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.95
BayesDel_addAF	Pathogenic	0.32	D
BayesDel_noAF	Pathogenic	0.22
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Benign	0.031	T
Eigen	Uncertain	0.60
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.87	D
M_CAP	Uncertain	0.15	D
MetaRNN	Uncertain	0.67	D
MetaSVM	Benign	-0.55	T
MutationAssessor	Benign	1.0	L
PhyloP100		4.5
PrimateAI	Pathogenic	0.85	D
PROVEAN	Benign	-0.67	N
REVEL	Uncertain	0.37
Sift	Uncertain	0.0020	D
Sift4G	Benign	0.20	T
Polyphen		1.0	D
Vest4		0.71
MutPred		0.30		Loss of MoRF binding (P = 0.0527)
MVP		0.71
MPC		0.50
ClinPred		0.82	D
GERP RS		4.5
Varity_R		0.36
gMVP		0.75
Mutation Taster		=67/33	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: rs587778202; hg19: chr19-42797191;