chr19-42272064-A-G
Variant summary
Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2
The NM_001386298.1(CIC):c.281A>G(p.Lys94Arg) variant causes a missense change. The variant allele was found at a frequency of 0.000303 in 398,950 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 Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.00039 ( 1 hom., cov: 33)
Exomes 𝑓: 0.00025 ( 0 hom. )
Consequence
CIC
NM_001386298.1 missense
NM_001386298.1 missense
Scores
5
5
Clinical Significance
Conservation
PhyloP100: 4.84
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 -13 ACMG points.
BP4
?
Computational evidence support a benign effect (MetaRNN=0.011375397).
BP6
?
Variant 19-42272064-A-G is Benign according to our data. Variant chr19-42272064-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 1301614.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}. Variant chr19-42272064-A-G is described in Lovd as [Likely_benign].
BS1
?
Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.000387 (59/152276) while in subpopulation SAS AF= 0.0116 (56/4822). AF 95% confidence interval is 0.00918. There are 1 homozygotes in gnomad4. There are 42 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
BS2
?
High AC in GnomAd at 60 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CIC | NM_001386298.1 | c.281A>G | p.Lys94Arg | missense_variant | 2/21 | ENST00000681038.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CIC | ENST00000681038.1 | c.281A>G | p.Lys94Arg | missense_variant | 2/21 | NM_001386298.1 | P1 | ||
CIC | ENST00000572681.6 | c.281A>G | p.Lys94Arg | missense_variant | 2/21 | 5 |
Frequencies
GnomAD3 genomes ? AF: 0.000394 AC: 60AN: 152158Hom.: 1 Cov.: 33
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GnomAD4 exome AF: 0.000251 AC: 62AN: 246674Hom.: 0 Cov.: 0 AF XY: 0.000288 AC XY: 36AN XY: 125112
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GnomAD4 genome ? AF: 0.000387 AC: 59AN: 152276Hom.: 1 Cov.: 33 AF XY: 0.000564 AC XY: 42AN XY: 74458
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3478
ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:1Benign:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Intellectual disability, autosomal dominant 45 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Al Jalila Children's Genomics Center, Al Jalila Childrens Speciality Hospital | Jan 08, 2020 | - - |
not provided Benign:1
Likely benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Feb 01, 2024 | CIC: BS1 - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Uncertain
D
BayesDel_noAF
Uncertain
Cadd
Uncertain
Dann
Uncertain
DEOGEN2
Benign
T;T
FATHMM_MKL
Uncertain
D
LIST_S2
Benign
T;T
M_CAP
Uncertain
D
MetaRNN
Benign
T;T
MutationTaster
Benign
N
Sift4G
Benign
T;T
Vest4
MVP
GERP RS
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at