19-42271989-G-A

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 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 Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0026 (4 hom., cov: 33)
  • Exomes 𝑓: 0.0030 (7 hom.)
• Consequence: CIC NM_001386298.1 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0054611266).
• BP6: Variant 19-42271989-G-A is Benign according to our data. Variant chr19-42271989-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 2585385.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.
• 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.
• BS2: High AC in GnomAd 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: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

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, criteria provided, single submitter

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;