19-42294851-GC-AT

Variant names:

• chr19-42294851-GC-AT
• NM_001386298.1:c.7214_7215delGCinsAT
• CIC p.Arg2405His

Variant summary

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

The NM_001386298.1(CIC):​c.7214_7215delGCinsAT​(p.Arg2405His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type MNV, and the frequency of such variant types in population databases may be underestimated and unreliable. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R2405C) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: CIC NM_001386298.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.50
• 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):

• complex neurodevelopmental disorder

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• intellectual disability, autosomal dominant 45

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Illumina, Labcorp Genetics (formerly Invitae)
• 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 0 ACMG points.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CIC	NM_001386298.1	MANE Select	c.7214_7215delGCinsAT	p.Arg2405His	missense	N/A	NP_001373227.1	Q96RK0-1
	CIC	NM_001304815.2		c.7214_7215delGCinsAT	p.Arg2405His	missense	N/A	NP_001291744.1	Q96RK0-1
	CIC	NM_001379480.1		c.7211_7212delGCinsAT	p.Arg2404His	missense	N/A	NP_001366409.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CIC	ENST00000681038.1	MANE Select	c.7214_7215delGCinsAT	p.Arg2405His	missense	N/A	ENSP00000505728.1	Q96RK0-1
	CIC	ENST00000575354.6	TSL:1	c.4487_4488delGCinsAT	p.Arg1496His	missense	N/A	ENSP00000458663.2	Q96RK0-2
	CIC	ENST00000940332.1		c.7211_7212delGCinsAT	p.Arg2404His	missense	N/A	ENSP00000610391.1

Frequencies

GnomAD3 genomes Cov.: 33

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		2.5

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chr19-42799003;