11-2884860-GGGGGCCGGGGCCGGGGCC-GGGGGCCGGGGCCGGGGCCGGGGCC

Position:

• chr11-2884860-GGGGGCCGGGGCCGGGGCC-GGGGGCCGGGGCCGGGGCCGGGGCC

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP6 BS2

The NM_001122630.2(CDKN1C):​c.596_597insGGCCCC​(p.Ala204_Pro205dup) variant causes a inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00097 in 143,322 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00097 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00016 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CDKN1C NM_001122630.2 inframe_insertion
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:3
• Conservation: PhyloP100: 1.73

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 Likely_benign. Variant got -5 ACMG points.

• BP6: Variant 11-2884860-G-GGGGGCC is Benign according to our data. Variant chr11-2884860-G-GGGGGCC is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 236968.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Benign=1, Uncertain_significance=2}.
• BS2: High AC in GnomAd4 at 139 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CDKN1C	NM_001122630.2	c.596_597insGGCCCC	p.Ala204_Pro205dup	inframe_insertion	2/4	ENST00000440480.8	NP_001116102.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CDKN1C	ENST00000440480.8	c.596_597insGGCCCC	p.Ala204_Pro205dup	inframe_insertion	2/4	1	NM_001122630.2	ENSP00000411257	A2

Frequencies

GnomAD3 genomes AF: 0.000970 AC: 139 AN: 143228 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00154

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000480

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00144

Gnomad SAS AF: 0.00524

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000556

Gnomad OTH AF: 0.00200

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.000156 AC: 137 AN: 879568 Hom.: 0 Cov.: 12 AF XY: 0.000168 AC XY: 70 AN XY: 415600

Gnomad4 AFR exome AF: 0.000351

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00103

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000136

Gnomad4 OTH exome AF: 0.000250

GnomAD4 genome AF: 0.000970 AC: 139 AN: 143322 Hom.: 0 Cov.: 32 AF XY: 0.00107 AC XY: 75 AN XY: 69870

Gnomad4 AFR AF: 0.00154

Gnomad4 AMR AF: 0.000479

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00144

Gnomad4 SAS AF: 0.00525

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000556

Gnomad4 OTH AF: 0.00198

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Beckwith-Wiedemann syndrome Uncertain:1 Benign:1

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Uncertain significance, criteria provided, single submitter	curation	Sema4, Sema4	May 25, 2021	- -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Mar 09, 2017

- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Sep 02, 2016

- -

CDKN1C-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 29, 2022

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

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;