rs587778207

Variant names:

• chr19-42293752-C-G
• NM_001386298.1:c.6683C>G

Your query was ambiguous. Multiple possible variants found:

• chr19-42293752-C-G
• chr19-42293752-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001386298.1(CIC):​c.6683C>G​(p.Pro2228Arg) 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. 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. P2228L) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: CIC NM_001386298.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.38

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3416987).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CIC	NM_001386298.1	c.6683C>G	p.Pro2228Arg	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.6683C>G	p.Pro2228Arg	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: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

May 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

CIC: PM2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.28
BayesDel_addAF	Pathogenic	0.36	D
BayesDel_noAF	Pathogenic	0.28
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.023	T;.;T;T
Eigen	Benign	0.11
Eigen_PC	Benign	0.045
FATHMM_MKL	Benign	0.34	N
LIST_S2	Benign	0.85	T;T;T;T
M_CAP	Uncertain	0.15	D
MetaRNN	Benign	0.34	T;T;T;T
MetaSVM	Benign	-0.76	T
MutationAssessor	Benign	1.6	.;.;L;.
PrimateAI	Uncertain	0.71	T
REVEL	Benign	0.21
Sift4G	Uncertain	0.014	D;D;D;D
Polyphen		1.0	.;.;D;.
Vest4		0.47
MutPred		0.18		.;.;Gain of MoRF binding (P = 0.0065);.;
MVP		0.91
MPC		0.40
ClinPred		0.93	D
GERP RS		4.3
Varity_R		0.078
gMVP		0.57

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr19-42797904;