19-42290914-C-T
Variant summary
Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_ModerateBP6_ModerateBS1BS2
The NM_001386298.1(CIC):c.4873C>T(p.Arg1625Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000459 in 1,613,572 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 Likely benign (★).
Frequency
Genomes: 𝑓 0.000079 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000042 ( 1 hom. )
Consequence
CIC
NM_001386298.1 missense
NM_001386298.1 missense
Scores
1
7
7
Clinical Significance
Conservation
PhyloP100: 0.492
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 -12 ACMG points.
BP4
?
Computational evidence support a benign effect (MetaRNN=0.1888859).
BP6
?
Variant 19-42290914-C-T is Benign according to our data. Variant chr19-42290914-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 133897.Status of the report is criteria_provided_single_submitter, 1 stars.
BS1
?
Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.0000788 (12/152332) while in subpopulation EAS AF= 0.00174 (9/5184). AF 95% confidence interval is 0.000905. There are 0 homozygotes in gnomad4. There are 6 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
BS2
?
High AC in GnomAd at 12 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CIC | NM_001386298.1 | c.4873C>T | p.Arg1625Trp | missense_variant | 11/21 | ENST00000681038.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CIC | ENST00000681038.1 | c.4873C>T | p.Arg1625Trp | missense_variant | 11/21 | NM_001386298.1 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000788 AC: 12AN: 152214Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.000129 AC: 32AN: 248862Hom.: 0 AF XY: 0.000104 AC XY: 14AN XY: 135116
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GnomAD4 exome AF: 0.0000424 AC: 62AN: 1461240Hom.: 1 Cov.: 33 AF XY: 0.0000399 AC XY: 29AN XY: 726920
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ClinVar
Significance: Likely benign
Submissions summary: Benign:1Other:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Inborn genetic diseases Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Sep 02, 2021 | This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. - |
not specified Other:1
not provided, no classification provided | reference population | ITMI | Sep 19, 2013 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Uncertain
T
BayesDel_noAF
Pathogenic
Cadd
Uncertain
Dann
Uncertain
DEOGEN2
Benign
T;.;T
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D;D;D
M_CAP
Uncertain
D
MetaRNN
Benign
T;T;T
MetaSVM
Benign
T
MutationTaster
Benign
D;N
PrimateAI
Uncertain
T
Sift4G
Uncertain
D;D;D
Polyphen
1.0
.;.;D
Vest4
MVP
MPC
0.44
ClinPred
T
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
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Calibrated prediction
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at