19-42293216-C-G

Variant names:

• chr19-42293216-C-G
• rs587778201
• NM_001386298.1:c.6457C>G

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001386298.1(CIC):​c.6457C>G​(p.Arg2153Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000208 in 1,444,064 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R2153W) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: CIC NM_001386298.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.41
• 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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2955434).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CIC	NM_001386298.1	c.6457C>G	p.Arg2153Gly	missense_variant	Exon 16 of 21	ENST00000681038.1	NP_001373227.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CIC	ENST00000681038.1	c.6457C>G	p.Arg2153Gly	missense_variant	Exon 16 of 21		NM_001386298.1	ENSP00000505728.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000956 AC: 2 AN: 209216 AF XY: 0.00000873

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000633

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000208 AC: 3 AN: 1444064 Hom.: 0 Cov.: 34 AF XY: 0.00000279 AC XY: 2 AN XY: 716964

African (AFR) AF: 0.00 AC: 0 AN: 33042

American (AMR) AF: 0.0000469 AC: 2 AN: 42668

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25752

East Asian (EAS) AF: 0.00 AC: 0 AN: 38646

South Asian (SAS) AF: 0.0000119 AC: 1 AN: 83840

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50338

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5480

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1104622

Other (OTH) AF: 0.00 AC: 0 AN: 59676

GnomAD4 genome Cov.: 33

ExAC AF: 0.00000832 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Uncertain	-0.030
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.012	T;.;T
Eigen	Benign	-0.13
Eigen_PC	Benign	-0.034
FATHMM_MKL	Benign	0.72	D
LIST_S2	Uncertain	0.87	D;D;D
M_CAP	Benign	0.030	D
MetaRNN	Benign	0.30	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.0	.;.;N
PhyloP100		2.4
PrimateAI	Uncertain	0.48	T
REVEL	Benign	0.17
Sift4G	Benign	0.38	T;T;T
Polyphen		0.61	.;.;P
Vest4		0.65
MutPred		0.19		.;.;Gain of relative solvent accessibility (P = 0.0249);
MVP		0.34
MPC		0.46
ClinPred		0.23	T
GERP RS		3.4
PromoterAI		-0.0094	Neutral
Varity_R		0.091
gMVP		0.53
Mutation Taster		=92/8	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: rs587778201; hg19: chr19-42797368;