19-42271989-G-A

Position:

• chr19-42271989-G-A

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BS1_Supporting BS2

The NM_001386298.1(CIC):​c.206G>A​(p.Arg69Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00283 in 399,176 control chromosomes in the GnomAD database, including 11 homozygotes. In-silico tool predicts a benign outcome for this variant. 8/9 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0026 (4 hom., cov: 33)
  • Exomes 𝑓: 0.0030 (7 hom.)
• Consequence: CIC NM_001386298.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1 B:1
• Conservation: PhyloP100: -0.685

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 Benign. Variant got -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0054611266).
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00262 (399/152308) while in subpopulation SAS AF= 0.0201 (97/4830). AF 95% confidence interval is 0.0168. There are 4 homozygotes in gnomad4. There are 207 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High AC in GnomAd4 at 399 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CIC	NM_001386298.1	c.206G>A	p.Arg69Gln	missense_variant	2/21	ENST00000681038.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CIC	ENST00000681038.1	c.206G>A	p.Arg69Gln	missense_variant	2/21		NM_001386298.1	P1
CIC	ENST00000572681.6	c.206G>A	p.Arg69Gln	missense_variant	2/21	5

Frequencies

GnomAD3 genomes AF: 0.00262 AC: 399 AN: 152190 Hom.: 4 Cov.: 33

Gnomad AFR AF: 0.000434

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00360

Gnomad ASJ AF: 0.00259

Gnomad EAS AF: 0.000962

Gnomad SAS AF: 0.0201

Gnomad FIN AF: 0.000848

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.00285

Gnomad OTH AF: 0.00382

GnomAD4 exome AF: 0.00295 AC: 729 AN: 246868 Hom.: 7 Cov.: 0 AF XY: 0.00293 AC XY: 367 AN XY: 125202

Gnomad4 AFR exome AF: 0.000696

Gnomad4 AMR exome AF: 0.00350

Gnomad4 ASJ exome AF: 0.00498

Gnomad4 EAS exome AF: 0.000131

Gnomad4 SAS exome AF: 0.0187

Gnomad4 FIN exome AF: 0.00129

Gnomad4 NFE exome AF: 0.00303

Gnomad4 OTH exome AF: 0.00323

GnomAD4 genome AF: 0.00262 AC: 399 AN: 152308 Hom.: 4 Cov.: 33 AF XY: 0.00278 AC XY: 207 AN XY: 74472

Gnomad4 AFR AF: 0.000433

Gnomad4 AMR AF: 0.00359

Gnomad4 ASJ AF: 0.00259

Gnomad4 EAS AF: 0.000964

Gnomad4 SAS AF: 0.0201

Gnomad4 FIN AF: 0.000848

Gnomad4 NFE AF: 0.00285

Gnomad4 OTH AF: 0.00378

Alfa AF: 0.00265 Hom.: 0

Bravo AF: 0.00194

TwinsUK AF: 0.00216 AC: 8

ALSPAC AF: 0.00259 AC: 10

ExAC AF: 0.00184 AC: 77

Asia WGS AF: 0.00520 AC: 19 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Intellectual disability, autosomal dominant 45 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Neuberg Centre For Genomic Medicine, NCGM

-

The missense variant c.206G>A (p.Arg69Gln) in CIC gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. This variant is reported with the allele frequency of 0.12% in the gnomad and 0.41% in 1000 genome database. The amino acid Arginine at position 69 is changed to a Glutamine changing protein sequence and it might alter its composition and physico-chemical properties. The residue is conserved across species. For these reasons, this variant has been classified as Uncertain Significance. -

CIC-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 22, 2019

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.25
CADD	Benign	5.6
DANN	Benign	0.80
DEOGEN2	Benign	0.0033	T;T
FATHMM_MKL	Benign	0.32	N
LIST_S2	Benign	0.54	T;T
MetaRNN	Benign	0.0055	T;T
MutationTaster	Benign	1.0	N
Sift4G	Benign	0.41	T;T
Vest4		0.074
MVP		0.58
GERP RS		-5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs188464728; hg19: chr19-42776141;