rs543847978
Positions:
Variant summary
Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBS1_SupportingBS2
The NM_001386298.1(CIC):c.5645C>A(p.Thr1882Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000527 in 1,614,002 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as not provided (no stars).
Frequency
Genomes: 𝑓 0.00017 ( 1 hom., cov: 33)
Exomes 𝑓: 0.000040 ( 1 hom. )
Consequence
CIC
NM_001386298.1 missense
NM_001386298.1 missense
Scores
1
5
9
Clinical Significance
Conservation
PhyloP100: 1.88
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 -9 ACMG points.
BP4
?
Computational evidence support a benign effect (MetaRNN=0.054989457).
BS1
?
Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.000171 (26/152350) while in subpopulation EAS AF= 0.00328 (17/5186). AF 95% confidence interval is 0.00209. There are 1 homozygotes in gnomad4. There are 12 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
BS2
?
High AC in GnomAd4 at 26 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CIC | NM_001386298.1 | c.5645C>A | p.Thr1882Lys | missense_variant | 13/21 | ENST00000681038.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CIC | ENST00000681038.1 | c.5645C>A | p.Thr1882Lys | missense_variant | 13/21 | NM_001386298.1 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.000171 AC: 26AN: 152232Hom.: 1 Cov.: 33
GnomAD3 genomes
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GnomAD3 exomes AF: 0.000171 AC: 43AN: 251122Hom.: 0 AF XY: 0.000155 AC XY: 21AN XY: 135848
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GnomAD4 exome AF: 0.0000404 AC: 59AN: 1461652Hom.: 1 Cov.: 34 AF XY: 0.0000330 AC XY: 24AN XY: 727142
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GnomAD4 genome ? AF: 0.000171 AC: 26AN: 152350Hom.: 1 Cov.: 33 AF XY: 0.000161 AC XY: 12AN XY: 74502
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ClinVar
Significance: not provided
Submissions summary: Other:1
Revision: no classification provided
LINK: link
Submissions by phenotype
not specified Other:1
not provided, no classification provided | reference population | ITMI | Sep 19, 2013 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
BayesDel_addAF
Benign
T
BayesDel_noAF
Pathogenic
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Benign
T;.;T
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Benign
D
LIST_S2
Benign
T;T;T
M_CAP
Benign
D
MetaRNN
Benign
T;T;T
MetaSVM
Benign
T
MutationTaster
Benign
D;D
PrimateAI
Uncertain
T
Sift4G
Benign
T;T;T
Polyphen
0.90
.;.;P
Vest4
MVP
MPC
0.46
ClinPred
T
GERP RS
Varity_R
gMVP
Splicing
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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