Genetic Variant CDKN1C:p.Pro199_Ala200insAlaPro (chr11-2884860-G-GGGGGCC) – ACMG Classification: Benign (-9 pts)

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP6BS1BS2

The NM_001122630.2(CDKN1C):c.591_596dupGGCCCC(p.Pro199_Ala200insAlaPro) variant causes a disruptive 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 disruptive_inframe_insertion

Scores

Not classified

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:3

Conservation

PhyloP100: 1.73

Variant links:

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]

CDKN1C links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -9 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}.

BS1

Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00097 (139/143322) while in subpopulation SAS AF= 0.00525 (24/4574). AF 95% confidence interval is 0.00362. There are 0 homozygotes in gnomad4. There are 75 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd4 at 139 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CDKN1C	NM_001122630.2 link	c.591_596dupGGCCCC	p.Pro199_Ala200insAlaPro	disruptive_inframe_insertion	Exon 2 of 4	ENST00000440480.8	NP_001116102.1	P49918-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CDKN1C	ENST00000440480.8 link	c.591_596dupGGCCCC	p.Pro199_Ala200insAlaPro	disruptive_inframe_insertion	Exon 2 of 4	1	NM_001122630.2	ENSP00000411257.2		P49918-2

Frequencies

GnomAD3 genomes

AF:

0.000970

AC:

139

AN:

143228

Hom.:

Cov.:

show subpopulations

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.:

Cov.:

AF XY:

0.000168

AC XY:

AN XY:

415600

show subpopulations

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.:

Cov.:

AF XY:

0.00107

AC XY:

AN XY:

69870

show subpopulations

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:2Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Beckwith-Wiedemann syndrome

Uncertain:1Benign:1

May 25, 2021

Sema4, Sema4

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: curation

- -

Jan 06, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Uncertain:1

Mar 09, 2017

Eurofins Ntd Llc (ga)

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified

Benign:1

Sep 02, 2016

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

CDKN1C-related disorder

Benign:1

Jun 29, 2022

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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

Name

Calibrated prediction

Score

Prediction

Splicing

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

11-2884860-GGGGGCCGGGGCCGGGGCC-GGGGGCCGGGGCCGGGGCCGGGGCC

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over