19-42289013-C-T

Variant names:

• chr19-42289013-C-T
• rs1135401823
• NM_001386298.1:c.3784C>T

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_001386298.1(CIC):​c.3784C>T​(p.Arg1262*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CIC NM_001386298.1 stop_gained
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 1.75
• Publications: 4 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: Pathogenic. The variant received 12 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 19-42289013-C-T is Pathogenic according to our data. Variant chr19-42289013-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 431168.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CIC	NM_001386298.1	c.3784C>T	p.Arg1262*	stop_gained	Exon 8 of 21	ENST00000681038.1	NP_001373227.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CIC	ENST00000681038.1	c.3784C>T	p.Arg1262*	stop_gained	Exon 8 of 21		NM_001386298.1	ENSP00000505728.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Intellectual disability, autosomal dominant 45 Pathogenic:1

Apr 21, 2022

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

not provided Pathogenic:1

Aug 21, 2017

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The R353X variant in the CIC gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The R353X variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). We interpret R353X as a pathogenic variant. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.48	D
BayesDel_noAF	Pathogenic	0.45
CADD	Pathogenic	39
DANN	Uncertain	1.0
Eigen	Pathogenic	0.80
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Uncertain	0.88	D
PhyloP100		1.7
Vest4		0.93
GERP RS		2.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Mutation Taster		=0/200	disease causing (ClinVar)

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: rs1135401823; hg19: chr19-42793165; COSMIC: COSV50639805; COSMIC: COSV50639805;