19-42271848-C-T

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BS1 BS2

The NM_001386298.1(CIC):c.65C>T(p.Pro22Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00117 in 398,648 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0010 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0013 (1 hom.)
• Consequence: CIC NM_001386298.1 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 4.25

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 -18 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.13777766).
• BP6: Variant 19-42271848-C-T is Benign according to our data. Variant chr19-42271848-C-T is described in ClinVar as [Benign]. Clinvar id is 2571046.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 = 0.000998 (152/152236) while in subpopulation NFE AF= 0.0015 (102/68028). AF 95% confidence interval is 0.00126. There are 0 homozygotes in gnomad4. There are 75 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd at 152 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CIC	NM_001386298.1	c.65C>T	p.Pro22Leu	missense_variant	2/21	ENST00000681038.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CIC	ENST00000681038.1	c.65C>T	p.Pro22Leu	missense_variant	2/21		NM_001386298.1	P1
CIC	ENST00000572681.6	c.65C>T	p.Pro22Leu	missense_variant	2/21	5

Frequencies

GnomAD3 genomes AF: 0.000998 AC: 152 AN: 152236 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000965

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00395

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00150

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00128 AC: 315 AN: 246412 Hom.: 1 Cov.: 0 AF XY: 0.00115 AC XY: 143 AN XY: 124872

Gnomad4 AFR exome AF: 0.000139

Gnomad4 AMR exome AF: 0.000404

Gnomad4 ASJ exome AF: 0.000108

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00379

Gnomad4 NFE exome AF: 0.00135

Gnomad4 OTH exome AF: 0.000977

GnomAD4 genome AF: 0.000998 AC: 152 AN: 152236 Hom.: 0 Cov.: 33 AF XY: 0.00101 AC XY: 75 AN XY: 74370

Gnomad4 AFR AF: 0.0000965

Gnomad4 AMR AF: 0.000262

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00395

Gnomad4 NFE AF: 0.00150

Gnomad4 OTH AF: 0.00

Alfa AF: 0.00318 Hom.: 0

Bravo AF: 0.000604

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.000259 AC: 1

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

CIC-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 05, 2021

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

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Jan 01, 2024

CIC: BS1, BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Uncertain	0.030
Cadd	Uncertain	25
Dann	Uncertain	0.99
DEOGEN2	Benign	0.014	T;T
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Benign	0.84	T;T
M_CAP	Pathogenic	0.40	D
MetaRNN	Benign	0.14	T;T
MutationTaster	Benign	0.99	D
Sift4G	Uncertain	0.025	D;D
Vest4		0.26
MVP		0.88
GERP RS		4.1
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: rs778531867; hg19: chr19-42776000;