11-2884966-ACCGCGACCGGAGCCGCGACCGGAG-ACCGCGACCGGAG

Position:

• chr11-2884966-ACCGCGACCGGAGCCGCGACCGGAG-ACCGCGACCGGAG

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The ENST00000440480.8(CDKN1C):​c.479_490del​(p.Ala160_Ala163del) variant causes a inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.23 in 980,206 control chromosomes in the GnomAD database, including 29,470 homozygotes. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. A160A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.21 (3243 hom., cov: 25)
  • Exomes 𝑓: 0.23 (26227 hom.)
• Consequence: CDKN1C ENST00000440480.8 inframe_deletion
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 0.593

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 -16 ACMG points.

• BP6: Variant 11-2884966-ACCGCGACCGGAG-A is Benign according to our data. Variant chr11-2884966-ACCGCGACCGGAG-A is described in ClinVar as [Likely_benign]. Clinvar id is 193042.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-2884966-ACCGCGACCGGAG-A is described in Lovd as [Benign]. Variant chr11-2884966-ACCGCGACCGGAG-A is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.27 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CDKN1C	NM_001122630.2	c.479_490del	p.Ala160_Ala163del	inframe_deletion	2/4	ENST00000440480.8	NP_001116102.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CDKN1C	ENST00000440480.8	c.479_490del	p.Ala160_Ala163del	inframe_deletion	2/4	1	NM_001122630.2	ENSP00000411257	A2

Frequencies

GnomAD3 genomes AF: 0.206 AC: 28094 AN: 136298 Hom.: 3242 Cov.: 25

Gnomad AFR AF: 0.0889

Gnomad AMI AF: 0.201

Gnomad AMR AF: 0.224

Gnomad ASJ AF: 0.309

Gnomad EAS AF: 0.104

Gnomad SAS AF: 0.189

Gnomad FIN AF: 0.178

Gnomad MID AF: 0.271

Gnomad NFE AF: 0.273

Gnomad OTH AF: 0.235

GnomAD3 exomes AF: 0.282 AC: 62 AN: 220 Hom.: 9 AF XY: 0.333 AC XY: 42 AN XY: 126

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.292

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.234 AC: 197281 AN: 843828 Hom.: 26227 AF XY: 0.236 AC XY: 95074 AN XY: 403256

Gnomad4 AFR exome AF: 0.0674

Gnomad4 AMR exome AF: 0.234

Gnomad4 ASJ exome AF: 0.292

Gnomad4 EAS exome AF: 0.0862

Gnomad4 SAS exome AF: 0.172

Gnomad4 FIN exome AF: 0.175

Gnomad4 NFE exome AF: 0.245

Gnomad4 OTH exome AF: 0.224

GnomAD4 genome AF: 0.206 AC: 28081 AN: 136378 Hom.: 3243 Cov.: 25 AF XY: 0.201 AC XY: 13336 AN XY: 66300

Gnomad4 AFR AF: 0.0888

Gnomad4 AMR AF: 0.224

Gnomad4 ASJ AF: 0.309

Gnomad4 EAS AF: 0.104

Gnomad4 SAS AF: 0.189

Gnomad4 FIN AF: 0.178

Gnomad4 NFE AF: 0.273

Gnomad4 OTH AF: 0.233

Asia WGS AF: 0.103 AC: 320 AN: 3080

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 07, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jul 16, 2014	- -

Beckwith-Wiedemann syndrome Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	curation	Sema4, Sema4	Dec 09, 2019	- -

not provided Benign:2

Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 14, 2019	This variant is associated with the following publications: (PMID: 20503313, 8655143) -

CDKN1C-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 19, 2024

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). -

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 18, 2022

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs565544512; hg19: chr11-2906196;