rs139337301

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001386298.1(CIC):c.4706C>T(p.Pro1569Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00108 in 1,612,318 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 0.00049 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0011 ( 1 hom. )

Consequence

CIC
NM_001386298.1 missense

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:2O:1

Conservation

PhyloP100: 1.58

Publications

6 publications found

Variant links:

COSMIC-nc: COSV105845003

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]

CIC Gene-Disease associations (from GenCC):

intellectual disability, autosomal dominant 45
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Illumina, Labcorp Genetics (formerly Invitae), G2P
cerebral folate deficiency
Inheritance: AD Classification: STRONG Submitted by: Franklin by Genoox
autosomal dominant non-syndromic intellectual disability
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

CIC links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.035318047).

BP6

Variant 19-42290747-C-T is Benign according to our data. Variant chr19-42290747-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 133896.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 = 0.000486 (74/152152) while in subpopulation NFE AF = 0.000838 (57/67990). AF 95% confidence interval is 0.000664. There are 0 homozygotes in GnomAd4. There are 35 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High AC in GnomAd4 at 74 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CIC	NM_001386298.1 link	c.4706C>T	p.Pro1569Leu	missense_variant	Exon 11 of 21	ENST00000681038.1	NP_001373227.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CIC	ENST00000681038.1 link	c.4706C>T	p.Pro1569Leu	missense_variant	Exon 11 of 21		NM_001386298.1	ENSP00000505728.1		A0A7P0T9K5

Frequencies

GnomAD3 genomes

AF:

0.000486

AC:

AN:

152152

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000362

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

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:

0.000838

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.000506

AC:

123

AN:

242934

AF XY:

0.000466

show subpopulations

Gnomad AFR exome

AF:

0.000203

Gnomad AMR exome

AF:

0.0000875

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000143

Gnomad NFE exome

AF:

0.00104

Gnomad OTH exome

AF:

0.000168

GnomAD4 exome

AF:

0.00114

AC:

1664

AN:

1460166

Hom.:

Cov.:

AF XY:

0.00111

AC XY:

808

AN XY:

726390

show subpopulations

African (AFR)

AF:

0.000149

AC:

AN:

33470

American (AMR)

AF:

0.0000672

AC:

AN:

44666

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26102

East Asian (EAS)

AF:

0.00

AC:

AN:

39674

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86236

European-Finnish (FIN)

AF:

0.0000957

AC:

AN:

52270

Middle Eastern (MID)

AF:

0.000174

AC:

AN:

5760

European-Non Finnish (NFE)

AF:

0.00146

AC:

1623

AN:

1111708

Other (OTH)

AF:

0.000431

AC:

AN:

60280

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.483

Heterozygous variant carriers

103

206

310

413

516

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

132

198

264

330

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000486

AC:

AN:

152152

Hom.:

Cov.:

AF XY:

0.000471

AC XY:

AN XY:

74334

show subpopulations

African (AFR)

AF:

0.000362

AC:

AN:

41446

American (AMR)

AF:

0.0000654

AC:

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3466

East Asian (EAS)

AF:

0.00

AC:

AN:

5186

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.000838

AC:

AN:

67990

Other (OTH)

AF:

0.000478

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.516

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000937

Hom.:

Bravo

AF:

0.000544

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.00234

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000703

AC:

ExAC

AF:

0.000471

AC:

EpiCase

AF:

0.000927

EpiControl

AF:

0.00101

ClinVar

Significance: Likely benign

Submissions summary: Benign:2Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Inborn genetic diseases

Benign:1

Jan 10, 2025

Ambry Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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 provided

Benign:1

Jan 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

CIC: BS1 -

not specified

Other:1

Sep 19, 2013

ITMI

Significance:not provided

Review Status:no classification provided

Collection Method:reference population

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.21

BayesDel_noAF

Uncertain

-0.080

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.017

T;.;T

Eigen

Benign

-0.60

Eigen_PC

Benign

-0.49

FATHMM_MKL

Benign

0.51

LIST_S2

Uncertain

0.90

D;D;D

M_CAP

Uncertain

0.11

MetaRNN

Benign

0.035

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.34

.;.;N

PhyloP100

1.6

PrimateAI

Uncertain

0.65

PROVEAN

Benign

-1.5

.;N;.

REVEL

Benign

0.037

Sift

Pathogenic

0.0

.;D;.

Sift4G

Benign

0.24

T;T;T

Polyphen

0.0050

.;.;B

Vest4

0.44

MVP

0.36

MPC

0.44

ClinPred

0.068

GERP RS

3.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.13

gMVP

0.18

Mutation Taster

=93/7

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over