rs587778209

Variant names:

• chr19-42287418-C-G
• rs587778209
• NM_001386298.1:c.3278C>G

Your query was ambiguous. Multiple possible variants found:

• chr19-42287418-C-G
• chr19-42287418-C-T

Variant summary

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

The NM_001386298.1(CIC):​c.3278C>G​(p.Ser1093Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,658 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts 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. S1093F) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: CIC NM_001386298.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.88
• Publications: 0 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=0.34583092).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CIC	NM_001386298.1	c.3278C>G	p.Ser1093Cys	missense_variant	Exon 5 of 21	ENST00000681038.1	NP_001373227.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CIC	ENST00000681038.1	c.3278C>G	p.Ser1093Cys	missense_variant	Exon 5 of 21		NM_001386298.1	ENSP00000505728.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461658 Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1 AN XY: 727138

African (AFR) AF: 0.0000299 AC: 1 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53200

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1112004

Other (OTH) AF: 0.00 AC: 0 AN: 60394

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.28
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Uncertain	-0.020
CADD	Pathogenic	28
DANN	Uncertain	0.98
DEOGEN2	Benign	0.027	T;.;T
Eigen	Uncertain	0.54
Eigen_PC	Uncertain	0.52
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.87	D;D;D
M_CAP	Benign	0.043	D
MetaRNN	Benign	0.35	T;T;T
MetaSVM	Benign	-0.48	T
MutationAssessor	Benign	0.69	.;.;N
PhyloP100		2.9
PrimateAI	Uncertain	0.72	T
PROVEAN	Benign	-1.9	.;N;.
REVEL	Uncertain	0.30
Sift	Uncertain	0.019	.;D;.
Sift4G	Uncertain	0.013	D;D;D
Polyphen		1.0	.;.;D
Vest4		0.43
MutPred		0.30		.;Loss of phosphorylation at S184 (P = 6e-04);Loss of phosphorylation at S184 (P = 6e-04);
MVP		0.62
MPC		0.37
ClinPred		0.56	D
GERP RS		4.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.8
Varity_R		0.13
gMVP		0.84
Mutation Taster		=80/20	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: rs587778209; hg19: chr19-42791570;