11-2884860-GGGGGCCGGGGCCGGGGCC-GGGGGCC

Position:

• chr11-2884860-GGGGGCCGGGGCCGGGGCC-GGGGGCC

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BS1 BS2

The NM_001122630.2(CDKN1C):​c.585_596del​(p.Ala202_Pro205del) variant causes a inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0235 in 1,022,736 control chromosomes in the GnomAD database, including 474 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.018 (38 hom., cov: 32)
  • Exomes 𝑓: 0.024 (436 hom.)
• Consequence: CDKN1C NM_001122630.2 inframe_deletion
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 1.91

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 11-2884860-GGGGGCCGGGGCC-G is Benign according to our data. Variant chr11-2884860-GGGGGCCGGGGCC-G is described in ClinVar as [Likely_benign]. Clinvar id is 236965.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-2884860-GGGGGCCGGGGCC-G is described in Lovd as [Benign]. Variant chr11-2884860-GGGGGCCGGGGCC-G is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0184 (2642/143306) while in subpopulation NFE AF= 0.0297 (1926/64742). AF 95% confidence interval is 0.0286. There are 38 homozygotes in gnomad4. There are 1227 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 2642 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CDKN1C	NM_001122630.2	c.585_596del	p.Ala202_Pro205del	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.585_596del	p.Ala202_Pro205del	inframe_deletion	2/4	1	NM_001122630.2	ENSP00000411257	A2

Frequencies

GnomAD3 genomes AF: 0.0185 AC: 2643 AN: 143212 Hom.: 38 Cov.: 32

Gnomad AFR AF: 0.00552

Gnomad AMI AF: 0.0227

Gnomad AMR AF: 0.0154

Gnomad ASJ AF: 0.0252

Gnomad EAS AF: 0.000820

Gnomad SAS AF: 0.00830

Gnomad FIN AF: 0.00922

Gnomad MID AF: 0.0296

Gnomad NFE AF: 0.0297

Gnomad OTH AF: 0.0205

GnomAD4 exome AF: 0.0244 AC: 21423 AN: 879430 Hom.: 436 AF XY: 0.0242 AC XY: 10041 AN XY: 415538

Gnomad4 AFR exome AF: 0.00222

Gnomad4 AMR exome AF: 0.00565

Gnomad4 ASJ exome AF: 0.0146

Gnomad4 EAS exome AF: 0.000195

Gnomad4 SAS exome AF: 0.00656

Gnomad4 FIN exome AF: 0.00526

Gnomad4 NFE exome AF: 0.0264

Gnomad4 OTH exome AF: 0.0211

GnomAD4 genome AF: 0.0184 AC: 2642 AN: 143306 Hom.: 38 Cov.: 32 AF XY: 0.0176 AC XY: 1227 AN XY: 69866

Gnomad4 AFR AF: 0.00550

Gnomad4 AMR AF: 0.0154

Gnomad4 ASJ AF: 0.0252

Gnomad4 EAS AF: 0.000823

Gnomad4 SAS AF: 0.00831

Gnomad4 FIN AF: 0.00922

Gnomad4 NFE AF: 0.0297

Gnomad4 OTH AF: 0.0203

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 31, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Nov 10, 2017	- -

not provided Benign:4

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2024	CDKN1C: BS1, BS2 -
Likely benign, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The CDKN1C p.Ala213_Pro216del variant was not identified in the literature nor was it identified in Cosmic. The variant was identified in dbSNP (ID: rs759134767), ClinVar (classified as benign by Invitae, Prevention Genetics and EGL Genetic Diagnostics) and LOVD 3.0. The variant was identified in control databases in 415 of 25528 chromosomes (6 homozygous) at a frequency of 0.016257 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: European (non-Finnish) in 344 of 13620 chromosomes (freq: 0.02526), Ashkenazi Jewish in 6 of 258 chromosomes (freq: 0.02326), Latino in 6 of 416 chromosomes (freq: 0.01442), Other in 10 of 752 chromosomes (freq: 0.0133), European (Finnish) in 6 of 962 chromosomes (freq: 0.006237) and African in 43 of 7844 chromosomes (freq: 0.005482); it was not observed in the East Asian or South Asian populations. The variant occurs outside the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. This variant is an in-frame deletion resulting in the removal of the APAP residues between codons 213-216 in a non-conserved repeat region with unknown function. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. Therefore it is classified as likely benign. -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 16, 2021	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

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	Feb 24, 2020	- -

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: rs759134767; hg19: chr11-2906090;