chr19-42271848-C-T
Variant summary
Our verdict is Benign. Variant got -18 ACMG points: 0P and 18B. BP4_ModerateBP6_Very_StrongBS1BS2
The NM_001386298.1(CIC):c.65C>T(p.Pro22Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00117 in 398,648 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).
Frequency
Genomes: 𝑓 0.0010 ( 0 hom., cov: 33)
Exomes 𝑓: 0.0013 ( 1 hom. )
Consequence
CIC
NM_001386298.1 missense
NM_001386298.1 missense
Scores
1
4
5
Clinical Significance
Conservation
PhyloP100: 4.25
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]
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ACMG classification
Classification made for transcript
Verdict is Benign. Variant got -18 ACMG points.
BP4
?
Computational evidence support a benign effect (MetaRNN=0.13777766).
BP6
?
Variant 19-42271848-C-T is Benign according to our data. Variant chr19-42271848-C-T is described in ClinVar as [Benign]. Clinvar id is 2571046.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BS1
?
Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000998 (152/152236) while in subpopulation NFE AF= 0.0015 (102/68028). AF 95% confidence interval is 0.00126. There are 0 homozygotes in gnomad4. There are 75 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
BS2
?
High AC in GnomAd at 152 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CIC | NM_001386298.1 | c.65C>T | p.Pro22Leu | missense_variant | 2/21 | ENST00000681038.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CIC | ENST00000681038.1 | c.65C>T | p.Pro22Leu | missense_variant | 2/21 | NM_001386298.1 | P1 | ||
CIC | ENST00000572681.6 | c.65C>T | p.Pro22Leu | missense_variant | 2/21 | 5 |
Frequencies
GnomAD3 genomes ? AF: 0.000998 AC: 152AN: 152236Hom.: 0 Cov.: 33
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GnomAD4 exome AF: 0.00128 AC: 315AN: 246412Hom.: 1 Cov.: 0 AF XY: 0.00115 AC XY: 143AN XY: 124872
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GnomAD4 genome ? AF: 0.000998 AC: 152AN: 152236Hom.: 0 Cov.: 33 AF XY: 0.00101 AC XY: 75AN XY: 74370
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ClinVar
Significance: Benign
Submissions summary: Benign:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
CIC-related disorder Benign:1
Benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Jan 05, 2021 | This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). - |
not provided Benign:1
Benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Jan 01, 2024 | CIC: BS1, BS2 - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Benign
T
BayesDel_noAF
Uncertain
Cadd
Uncertain
Dann
Uncertain
DEOGEN2
Benign
T;T
FATHMM_MKL
Uncertain
D
LIST_S2
Benign
T;T
M_CAP
Pathogenic
D
MetaRNN
Benign
T;T
MutationTaster
Benign
D
Sift4G
Uncertain
D;D
Vest4
MVP
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at