rs185048610

Positions:

• chr19-42292700-T-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_001386298.1(CIC):​c.6037T>A​(p.Ser2013Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000518 in 1,613,574 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.00080 (2 hom., cov: 33)
  • Exomes 𝑓: 0.00049 (4 hom.)
• Consequence: CIC NM_001386298.1 missense
• Clinical Significance: Benign criteria provided, single submitter B:1 O:1
• Conservation: PhyloP100: 2.39

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0060694814).
• BP6: Variant 19-42292700-T-A is Benign according to our data. Variant chr19-42292700-T-A is described in ClinVar as [Benign]. Clinvar id is 133908.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.000803 (122/152012) while in subpopulation EAS AF= 0.0198 (102/5152). AF 95% confidence interval is 0.0167. There are 2 homozygotes in gnomad4. There are 61 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 122 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CIC	NM_001386298.1	c.6037T>A	p.Ser2013Thr	missense_variant	15/21	ENST00000681038.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CIC	ENST00000681038.1	c.6037T>A	p.Ser2013Thr	missense_variant	15/21		NM_001386298.1	P1

Frequencies

GnomAD3 genomes AF: 0.000810 AC: 123 AN: 151894 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.000266

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0199

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00192

GnomAD3 exomes AF: 0.00180 AC: 451 AN: 251046 Hom.: 2 AF XY: 0.00172 AC XY: 234 AN XY: 135738

Gnomad AFR exome AF: 0.000370

Gnomad AMR exome AF: 0.000231

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0233

Gnomad SAS exome AF: 0.0000653

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00114

GnomAD4 exome AF: 0.000489 AC: 714 AN: 1461562 Hom.: 4 Cov.: 35 AF XY: 0.000466 AC XY: 339 AN XY: 727108

Gnomad4 AFR exome AF: 0.000239

Gnomad4 AMR exome AF: 0.000246

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0148

Gnomad4 SAS exome AF: 0.0000464

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000360

Gnomad4 OTH exome AF: 0.00166

GnomAD4 genome AF: 0.000803 AC: 122 AN: 152012 Hom.: 2 Cov.: 33 AF XY: 0.000821 AC XY: 61 AN XY: 74336

Gnomad4 AFR AF: 0.000265

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0198

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00190

Alfa AF: 0.000256 Hom.: 0

Bravo AF: 0.00102

ExAC AF: 0.00146 AC: 177

Asia WGS AF: 0.00491 AC: 18 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Dec 31, 2019

- -

not specified Other:1

not provided, no classification provided

reference population

ITMI

Sep 19, 2013

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.090
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.21
CADD	Benign	22
DANN	Benign	0.84
DEOGEN2	Benign	0.0078	T;.;T
Eigen	Benign	-0.50
Eigen_PC	Benign	-0.34
FATHMM_MKL	Benign	0.53	D
LIST_S2	Benign	0.59	T;T;T
MetaRNN	Benign	0.0061	T;T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	N;N
PrimateAI	Uncertain	0.56	T
Sift4G	Benign	0.12	T;T;T
Polyphen		0.0	.;.;B
Vest4		0.47
MVP		0.16
MPC		0.11
ClinPred		0.0077	T
GERP RS		1.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.15
gMVP		0.26

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

LitVar

Other links and lift over

dbSNP: rs185048610; hg19: chr19-42796852; COSMIC: COSV50553259; COSMIC: COSV50553259;