rs188494894

Positions:

• chr11-2885573-C-T

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 0P and 7B. BP4_Moderate BP6 BS2

The ENST00000414822.8(CDKN1C):​c.-84G>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00818 in 1,504,334 control chromosomes in the GnomAD database, including 78 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0059 (4 hom., cov: 33)
  • Exomes 𝑓: 0.0084 (74 hom.)
• Consequence: CDKN1C ENST00000414822.8 5_prime_UTR
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:4
• Conservation: PhyloP100: 0.885

Genes affected

CDKN1C (HGNC:1786): (cyclin dependent kinase inhibitor 1C) This gene is imprinted, with preferential expression of the maternal allele. The encoded protein is a tight-binding, strong inhibitor of several G1 cyclin/Cdk complexes and a negative regulator of cell proliferation. Mutations in this gene are implicated in sporadic cancers and Beckwith-Wiedemann syndorome, suggesting that this gene is a tumor suppressor candidate. Three transcript variants encoding two different isoforms have been found for this gene. [provided by RefSeq, Oct 2010]

ACMG classification

Verdict is Benign. Variant got -7 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.4).
• BP6: Variant 11-2885573-C-T is Benign according to our data. Variant chr11-2885573-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 236948.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1, Benign=3}. Variant chr11-2885573-C-T is described in Lovd as [Likely_benign].
• BS2: High AC in GnomAd4 at 898 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CDKN1C	NM_001122630.2	c.-11+61G>A		intron_variant		ENST00000440480.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CDKN1C	ENST00000440480.8	c.-11+61G>A		intron_variant		1	NM_001122630.2	A2

Frequencies

GnomAD3 genomes AF: 0.00590 AC: 898 AN: 152172 Hom.: 4 Cov.: 33

Gnomad AFR AF: 0.00142

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00942

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00103

Gnomad FIN AF: 0.00283

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00936

Gnomad OTH AF: 0.00958

GnomAD4 exome AF: 0.00844 AC: 11406 AN: 1352044 Hom.: 74 Cov.: 25 AF XY: 0.00809 AC XY: 5388 AN XY: 665660

Gnomad4 AFR exome AF: 0.00155

Gnomad4 AMR exome AF: 0.00873

Gnomad4 ASJ exome AF: 0.000375

Gnomad4 EAS exome AF: 0.0000282

Gnomad4 SAS exome AF: 0.000654

Gnomad4 FIN exome AF: 0.00382

Gnomad4 NFE exome AF: 0.00985

Gnomad4 OTH exome AF: 0.00783

GnomAD4 genome AF: 0.00590 AC: 898 AN: 152290 Hom.: 4 Cov.: 33 AF XY: 0.00584 AC XY: 435 AN XY: 74454

Gnomad4 AFR AF: 0.00142

Gnomad4 AMR AF: 0.00941

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00104

Gnomad4 FIN AF: 0.00283

Gnomad4 NFE AF: 0.00937

Gnomad4 OTH AF: 0.00948

Alfa AF: 0.00783 Hom.: 2

Bravo AF: 0.00681

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Beckwith-Wiedemann syndrome Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Nov 22, 2022	- -
Benign, criteria provided, single submitter	curation	Sema4, Sema4	Sep 17, 2020	- -

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Feb 27, 2017	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2024	CDKN1C: BS1, BS2 -

IMAGe syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Baylor Genetics

Jun 08, 2018

This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.40
CADD	Benign	16
DANN	Benign	0.96

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: rs188494894; hg19: chr11-2906803;