19-42293721-A-G

Variant names:

• chr19-42293721-A-G
• rs587778205
• NM_001386298.1:c.6652A>G

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.6652A>G​(p.Ser2218Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as not provided (no stars).

• Frequency: Genomes: not found (cov: 33)
• Consequence: CIC NM_001386298.1 missense
• Clinical Significance: not provided no classification provided O:1
• Conservation: PhyloP100: 1.07
• 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.09527066).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CIC	NM_001386298.1	c.6652A>G	p.Ser2218Gly	missense_variant	Exon 17 of 21	ENST00000681038.1	NP_001373227.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CIC	ENST00000681038.1	c.6652A>G	p.Ser2218Gly	missense_variant	Exon 17 of 21		NM_001386298.1	ENSP00000505728.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

ClinVar

Significance: not provided

Submissions summary: Other:1

Revision: no classification provided

Submissions by phenotype

not specified Other:1

Sep 19, 2013

ITMI

Significance: not provided

Review Status: no classification provided

Collection Method: reference population

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.044
BayesDel_addAF	Uncertain	0.053	T
BayesDel_noAF	Benign	-0.16
CADD	Benign	16
DANN	Benign	0.65
DEOGEN2	Benign	0.0053	T;.;T;T
Eigen	Benign	-0.54
Eigen_PC	Benign	-0.40
FATHMM_MKL	Benign	0.069	N
LIST_S2	Benign	0.60	T;T;T;T
M_CAP	Uncertain	0.10	D
MetaRNN	Benign	0.095	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.34	.;.;N;.
PhyloP100		1.1
PrimateAI	Uncertain	0.62	T
PROVEAN	Benign	-1.2	.;N;.;.
REVEL	Benign	0.091
Sift	Uncertain	0.027	.;D;.;.
Sift4G	Benign	0.43	T;T;T;T
Polyphen		0.0	.;.;B;.
Vest4		0.10
MutPred		0.17		.;.;Loss of phosphorylation at S1309 (P = 0.005);.;
MVP		0.37
MPC		0.060
ClinPred		0.068	T
GERP RS		3.1
PromoterAI		-0.095	Neutral
Varity_R		0.030
gMVP		0.16
Mutation Taster		=93/7	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: rs587778205; hg19: chr19-42797873;