19-42290695-G-C

Variant names:

• chr19-42290695-G-C
• rs587778199
• NM_001386298.1:c.4654G>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001386298.1(CIC):​c.4654G>C​(p.Gly1552Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,696 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G1552S) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: CIC NM_001386298.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.276
• Publications: 1 publications found

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

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.10025823).

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CIC	NM_001386298.1	MANE Select	c.4654G>C	p.Gly1552Arg	missense	Exon 11 of 21	NP_001373227.1
	CIC	NM_001304815.2		c.4654G>C	p.Gly1552Arg	missense	Exon 11 of 21	NP_001291744.1
	CIC	NM_001379480.1		c.4654G>C	p.Gly1552Arg	missense	Exon 11 of 21	NP_001366409.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CIC	ENST00000681038.1	MANE Select	c.4654G>C	p.Gly1552Arg	missense	Exon 11 of 21	ENSP00000505728.1
	CIC	ENST00000575354.6	TSL:1	c.1927G>C	p.Gly643Arg	missense	Exon 10 of 20	ENSP00000458663.2
	CIC	ENST00000940332.1		c.4654G>C	p.Gly1552Arg	missense	Exon 11 of 21	ENSP00000610391.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460696 Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1 AN XY: 726666

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26118

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52408

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5760

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111902

Other (OTH) AF: 0.00 AC: 0 AN: 60356

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	CIC-related neurodevelopmental disorders (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Uncertain	0.037	T
BayesDel_noAF	Benign	-0.18
CADD	Benign	17
DANN	Benign	0.61
DEOGEN2	Benign	0.017	T
Eigen	Benign	-0.53
Eigen_PC	Benign	-0.45
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Uncertain	0.88	D
M_CAP	Uncertain	0.10	D
MetaRNN	Benign	0.10	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N
PhyloP100		0.28
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.033
Sift	Benign	0.043	D
Sift4G	Benign	0.27	T
Polyphen		0.31	B
Vest4		0.27
MutPred		0.15		Gain of methylation at G643 (P = 0.0284)
MVP		0.40
MPC		0.093
ClinPred		0.12	T
GERP RS		2.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.043
gMVP		0.22
Mutation Taster		=95/5	polymorphism

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

Other links and lift over

dbSNP: rs587778199; hg19: chr19-42794847;