NM_001386298.1:c.281A>G

Variant names:

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

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:1

Conservation

PhyloP100: 4.84

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]

CIC links:

Genome browser will be placed here

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: {Uncertain_significance=2, Likely_benign=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 GnomAd4 at 59 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CIC	NM_001386298.1 link	c.281A>G	p.Lys94Arg	missense_variant	Exon 2 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.281A>G	p.Lys94Arg	missense_variant	Exon 2 of 21		NM_001386298.1	ENSP00000505728.1		A0A7P0T9K5
CIC	ENST00000572681.6 link	c.281A>G	p.Lys94Arg	missense_variant	Exon 2 of 21	5		ENSP00000459719.1		I3L2J0

Frequencies

GnomAD3 genomes

AF:

0.000394

AC:

AN:

152158

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.0118

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.000251

AC:

AN:

246674

Hom.:

Cov.:

AF XY:

0.000288

AC XY:

AN XY:

125112

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:

0.0151

Gnomad4 FIN exome

AF:

0.0000480

Gnomad4 NFE exome

AF:

0.0000632

Gnomad4 OTH exome

AF:

0.000244

GnomAD4 genome

AF:

0.000387

AC:

AN:

152276

Hom.:

Cov.:

AF XY:

0.000564

AC XY:

AN XY:

74458

show subpopulations

Gnomad4 AFR

AF:

0.0000481

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.0116

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000208

Hom.:

Bravo

AF:

0.0000718

ExAC

AF:

0.000125

AC:

Asia WGS

AF:

0.00462

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Intellectual disability, autosomal dominant 45

Uncertain:2

Jan 08, 2020

Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Neuberg Centre For Genomic Medicine, NCGM

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The missense c.281A>G (p.Lys94Arg) variant in CIC gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. The p.Lys94Arg variant is present with allele frequency of 0% in gnomAD Exomes. This variant has been submitted to the ClinVar database as Uncertain Significance. Computational evidence (SIFT - Damaging and MutationTaster - Polymorphism) predicts conflicting evidence on protein structure and function for this variant. The reference amino acid at this position on CIC gene is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The amino acid Lys at position 94 is changed to a Arg changing protein sequence and it might alter its composition and physico-chemical properties. For these reasons, this variant has been classified as Variant of Uncertain Significance (VUS). -

not provided

Benign:1

Dec 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

CIC: BS1 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Uncertain

0.14

BayesDel_noAF

Uncertain

-0.030

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Benign

0.0059

T;T

FATHMM_MKL

Uncertain

0.83

LIST_S2

Benign

0.74

T;T

M_CAP

Uncertain

0.22

MetaRNN

Benign

0.011

T;T

Sift4G

Benign

0.37

T;T

Vest4

0.20

MVP

0.83

GERP RS

4.1

Splicing

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over