19-42271919-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001386298.1(CIC):c.136G>A(p.Glu46Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000714 in 399,030 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 7/10 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00060 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00078 (0 hom.)
• Consequence: CIC NM_001386298.1 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.260

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0329414).
• BP6: Variant 19-42271919-G-A is Benign according to our data. Variant chr19-42271919-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 1879442.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000604 (92/152294) while in subpopulation NFE AF= 0.00097 (66/68018). AF 95% confidence interval is 0.000782. There are 0 homozygotes in gnomad4. There are 40 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd at 92 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CIC	NM_001386298.1	c.136G>A	p.Glu46Lys	missense_variant	2/21	ENST00000681038.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CIC	ENST00000681038.1	c.136G>A	p.Glu46Lys	missense_variant	2/21		NM_001386298.1	P1
CIC	ENST00000572681.6	c.136G>A	p.Glu46Lys	missense_variant	2/21	5

Frequencies

GnomAD3 genomes AF: 0.000605 AC: 92 AN: 152176 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000193

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000458

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00104

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000970

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.000782 AC: 193 AN: 246736 Hom.: 0 Cov.: 0 AF XY: 0.000759 AC XY: 95 AN XY: 125112

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000672

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00129

Gnomad4 NFE exome AF: 0.000878

Gnomad4 OTH exome AF: 0.00134

GnomAD4 genome AF: 0.000604 AC: 92 AN: 152294 Hom.: 0 Cov.: 33 AF XY: 0.000537 AC XY: 40 AN XY: 74476

Gnomad4 AFR AF: 0.000193

Gnomad4 AMR AF: 0.000457

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00104

Gnomad4 NFE AF: 0.000970

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000659 Hom.: 0

Bravo AF: 0.000552

TwinsUK AF: 0.00135 AC: 5

ALSPAC AF: 0.00156 AC: 6

ExAC AF: 0.000198 AC: 7

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

CIC-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 26, 2022

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). -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Jan 01, 2024

CIC: BS1 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Uncertain	-0.070
Cadd	Benign	21
Dann	Uncertain	0.99
DEOGEN2	Benign	0.0055	T;T
FATHMM_MKL	Benign	0.19	N
LIST_S2	Benign	0.68	T;T
M_CAP	Benign	0.043	D
MetaRNN	Benign	0.033	T;T
MutationTaster	Benign	1.0	N
Sift4G	Benign	0.73	T;T
Vest4		0.22
MVP		0.63
GERP RS		2.4

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs117565967; hg19: chr19-42776071; COSMIC: COSV105942180;