rs587778205

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001386298.1(CIC):ā€‹c.6652A>Cā€‹(p.Ser2218Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000186 in 1,612,818 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: š‘“ 0.0000066 ( 0 hom., cov: 33)
Exomes š‘“: 0.0000014 ( 0 hom. )

Consequence

CIC
NM_001386298.1 missense

Scores

6
13

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.07
Variant links:
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 Uncertain_significance. Variant got 0 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.12683427).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
CICNM_001386298.1 linkc.6652A>C p.Ser2218Arg missense_variant 17/21 ENST00000681038.1 NP_001373227.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
CICENST00000681038.1 linkc.6652A>C p.Ser2218Arg missense_variant 17/21 NM_001386298.1 ENSP00000505728.1 A0A7P0T9K5

Frequencies

GnomAD3 genomes
AF:
0.00000657
AC:
1
AN:
152250
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000147
Gnomad OTH
AF:
0.00
GnomAD4 exome
AF:
0.00000137
AC:
2
AN:
1460568
Hom.:
0
Cov.:
33
AF XY:
0.00000138
AC XY:
1
AN XY:
726600
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000180
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.00000657
AC:
1
AN:
152250
Hom.:
0
Cov.:
33
AF XY:
0.0000134
AC XY:
1
AN XY:
74380
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000147
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.00000756

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
0.44
BayesDel_addAF
Uncertain
0.11
D
BayesDel_noAF
Benign
-0.090
CADD
Benign
21
DANN
Uncertain
0.98
DEOGEN2
Benign
0.012
T;.;T;T
Eigen
Benign
-0.54
Eigen_PC
Benign
-0.40
FATHMM_MKL
Benign
0.63
D
LIST_S2
Benign
0.81
T;T;T;T
M_CAP
Uncertain
0.16
D
MetaRNN
Benign
0.13
T;T;T;T
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
0.0
.;.;N;.
PrimateAI
Uncertain
0.66
T
PROVEAN
Benign
-1.1
.;N;.;.
REVEL
Benign
0.076
Sift
Uncertain
0.0010
.;D;.;.
Sift4G
Benign
0.073
T;T;T;D
Polyphen
0.0
.;.;B;.
Vest4
0.28
MutPred
0.29
.;.;Loss of phosphorylation at S1309 (P = 0.005);.;
MVP
0.34
MPC
0.072
ClinPred
0.15
T
GERP RS
3.1
Varity_R
0.059
gMVP
0.28

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.020
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs587778205; hg19: chr19-42797873; API