dbSNP rs141764284: CIC:p.Gly1368Ser (chr19-42289862-G-A) – ACMG Classification: Benign (-20 pts)

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.4102G>A(p.Gly1368Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000762 in 1,604,516 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0032 ( 3 hom., cov: 33)

Exomes 𝑓: 0.00050 ( 1 hom. )

Consequence

CIC
NM_001386298.1 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3O:1

Conservation

PhyloP100: -0.140

Publications

5 publications found

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 Gene-Disease associations (from GenCC):

complex neurodevelopmental disorder
Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
intellectual disability, autosomal dominant 45
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, Illumina
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=0.002650082).

BP6

Variant 19-42289862-G-A is Benign according to our data. Variant chr19-42289862-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 133922.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00322 (490/152276) while in subpopulation AFR AF = 0.0108 (448/41546). AF 95% confidence interval is 0.00996. There are 3 homozygotes in GnomAd4. There are 251 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High AC in GnomAd4 at 490 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001386298.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CIC	NM_001386298.1	MANE Select	c.4102G>A	p.Gly1368Ser	missense	Exon 10 of 21	NP_001373227.1	Q96RK0-1
CIC	NM_001304815.2		c.4102G>A	p.Gly1368Ser	missense	Exon 10 of 21	NP_001291744.1	Q96RK0-1
CIC	NM_001379480.1		c.4102G>A	p.Gly1368Ser	missense	Exon 10 of 21	NP_001366409.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CIC	ENST00000681038.1	MANE Select	c.4102G>A	p.Gly1368Ser	missense	Exon 10 of 21	ENSP00000505728.1	Q96RK0-1
CIC	ENST00000575354.6	TSL:1	c.1375G>A	p.Gly459Ser	missense	Exon 9 of 20	ENSP00000458663.2	Q96RK0-2
CIC	ENST00000940332.1		c.4102G>A	p.Gly1368Ser	missense	Exon 10 of 21	ENSP00000610391.1

Frequencies

GnomAD3 genomes

AF:

0.00321

AC:

488

AN:

152158

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0108

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000851

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:

0.000309

Gnomad OTH

AF:

0.00383

GnomAD2 exomes

AF:

0.00103

AC:

241

AN:

233722

AF XY:

0.000755

show subpopulations

Gnomad AFR exome

AF:

0.0129

Gnomad AMR exome

AF:

0.000826

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000218

Gnomad OTH exome

AF:

0.000519

GnomAD4 exome

AF:

0.000505

AC:

733

AN:

1452240

Hom.:

Cov.:

AF XY:

0.000437

AC XY:

315

AN XY:

721264

show subpopulations

African (AFR)

AF:

0.0131

AC:

438

AN:

33392

American (AMR)

AF:

0.000834

AC:

AN:

43144

Ashkenazi Jewish (ASJ)

AF:

0.0000386

AC:

AN:

25874

East Asian (EAS)

AF:

0.00

AC:

AN:

39408

South Asian (SAS)

AF:

0.0000476

AC:

AN:

84092

European-Finnish (FIN)

AF:

0.0000570

AC:

AN:

52668

Middle Eastern (MID)

AF:

0.000695

AC:

AN:

5754

European-Non Finnish (NFE)

AF:

0.000169

AC:

187

AN:

1107812

Other (OTH)

AF:

0.000998

AC:

AN:

60096

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.463

Heterozygous variant carriers

114

152

190

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

110

<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:

0.00322

AC:

490

AN:

152276

Hom.:

Cov.:

AF XY:

0.00337

AC XY:

251

AN XY:

74450

show subpopulations

African (AFR)

AF:

0.0108

AC:

448

AN:

41546

American (AMR)

AF:

0.000850

AC:

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5182

South Asian (SAS)

AF:

0.00

AC:

AN:

4816

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10614

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000309

AC:

AN:

68030

Other (OTH)

AF:

0.00379

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

110

138

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:

0.00174

Hom.:

Bravo

AF:

0.00374

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.0127

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.00120

AC:

145

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.058

BayesDel_addAF

Benign

-0.43

BayesDel_noAF

Benign

-0.38

CADD

Benign

2.5

(source)

DANN

Benign

0.73

DEOGEN2

Benign

0.0048

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.027

LIST_S2

Benign

0.72

MetaRNN

Benign

0.0027

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.0

PhyloP100

-0.14

PrimateAI

Benign

0.35

PROVEAN

Benign

-0.92

REVEL

Benign

0.12

Sift

Benign

0.24

Sift4G

Benign

0.75

Polyphen

0.0010

Vest4

0.14

MVP

0.40

MPC

0.078

ClinPred

0.00084

GERP RS

-4.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.026

gMVP

0.34

Mutation Taster

=92/8

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over