11-2884911-AGCCGGG-AGCCGGGGCCGGG

Variant names:

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP3BP6BS1BS2

The NM_001122630.2(CDKN1C):c.540_545dupCCCGGC(p.Ala182_Pro183insProAla) variant causes a disruptive inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000215 in 803,752 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. A182A) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00010 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00023 ( 1 hom. )

Consequence

CDKN1C
NM_001122630.2 disruptive_inframe_insertion

Scores

Not classified

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:1

Conservation

PhyloP100: -1.04

Publications

0 publications found

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 Gene-Disease associations (from GenCC):

Beckwith-Wiedemann syndrome
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
IMAGe syndrome
Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, Illumina, G2P, Ambry Genetics
rhabdomyosarcoma
Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
Beckwith-Wiedemann syndrome due to CDKN1C mutation
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
intrauterine growth restriction-short stature-early adult-onset diabetes syndrome
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
Silver-Russell syndrome
Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

CDKN1C links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -10 ACMG points.

BP3

Nonframeshift variant in repetitive region in NM_001122630.2

BP6

Variant 11-2884911-A-AGCCGGG is Benign according to our data. Variant chr11-2884911-A-AGCCGGG is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 454015.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000103 (12/117036) while in subpopulation NFE AF = 0.000218 (12/54922). AF 95% confidence interval is 0.000126. There are 0 homozygotes in GnomAd4. There are 4 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High AC in GnomAd4 at 12 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CDKN1C	NM_001122630.2 link	c.540_545dupCCCGGC	p.Ala182_Pro183insProAla	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.540_545dupCCCGGC	p.Ala182_Pro183insProAla	disruptive_inframe_insertion	Exon 2 of 4	1	NM_001122630.2	ENSP00000411257.2		P49918-2

Frequencies

GnomAD3 genomes

AF:

0.000103

AC:

AN:

116968

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000218

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.000234

AC:

161

AN:

686716

Hom.:

Cov.:

AF XY:

0.000226

AC XY:

AN XY:

323692

show subpopulations

African (AFR)

AF:

0.0000777

AC:

AN:

12874

American (AMR)

AF:

0.00

AC:

AN:

2732

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

5892

East Asian (EAS)

AF:

0.000163

AC:

AN:

6146

South Asian (SAS)

AF:

0.00

AC:

AN:

13666

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6912

Middle Eastern (MID)

AF:

0.00

AC:

AN:

1562

European-Non Finnish (NFE)

AF:

0.000248

AC:

152

AN:

612612

Other (OTH)

AF:

0.000288

AC:

AN:

24320

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000103

AC:

AN:

117036

Hom.:

Cov.:

AF XY:

0.0000700

AC XY:

AN XY:

57154

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30344

American (AMR)

AF:

0.00

AC:

AN:

12634

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2882

East Asian (EAS)

AF:

0.00

AC:

AN:

3960

South Asian (SAS)

AF:

0.00

AC:

AN:

3560

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6290

Middle Eastern (MID)

AF:

0.00

AC:

AN:

178

European-Non Finnish (NFE)

AF:

0.000218

AC:

AN:

54922

Other (OTH)

AF:

0.00

AC:

AN:

1638

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

CDKN1C-related disorder

Uncertain:1

Oct 14, 2022

PreventionGenetics, part of Exact Sciences

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The CDKN1C c.573_578dup6 variant is predicted to result in an in-frame duplication (p.Ala193_Pro194dup). To our knowledge, this particular variant has not been reported in the literature or in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. However, other variants resulting in the same impact on the protein (p.Ala193_Pro194dup) has been reported in a total of 4 heterozygous individuals in gnomAD (https://gnomad.broadinstitute.org/region/11-2906121-2906161). Furthermore, this variant is interpreted as likely benign in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/454015/). While we suspect this variant to be benign, at this time we interpret its clinical significance as uncertain due to the absence of conclusive functional and genetic evidence. -

Beckwith-Wiedemann syndrome

Benign:1

Jan 14, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

-1.0

Mutation Taster

=82/18

polymorphism

(source)

Splicing

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over