NM_001122630.2:c.467_490dupCTCCGGTCGCGGCTCCGGTCGCGG

Variant names:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP6BS1BS2

The NM_001122630.2(CDKN1C):c.467_490dupCTCCGGTCGCGGCTCCGGTCGCGG(p.Ala156_Ala163dup) variant causes a conservative inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000173 in 981,992 control chromosomes in the GnomAD database, with no homozygous occurrence. It is difficult to determine the true allele frequency of this variant because it is of type INS_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. V164V) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000051 ( 0 hom., cov: 26)

Exomes 𝑓: 0.000012 ( 0 hom. )

Consequence

CDKN1C
NM_001122630.2 conservative_inframe_insertion

Scores

Not classified

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:1

Conservation

PhyloP100: -0.200

Publications

8 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 -9 ACMG points.

BP6

Variant 11-2884966-A-ACCGCGACCGGAGCCGCGACCGGAG is Benign according to our data. Variant chr11-2884966-A-ACCGCGACCGGAGCCGCGACCGGAG is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 454007. Variant chr11-2884966-A-ACCGCGACCGGAGCCGCGACCGGAG is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 454007. Variant chr11-2884966-A-ACCGCGACCGGAGCCGCGACCGGAG is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 454007. Variant chr11-2884966-A-ACCGCGACCGGAGCCGCGACCGGAG is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 454007. Variant chr11-2884966-A-ACCGCGACCGGAGCCGCGACCGGAG is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 454007. Variant chr11-2884966-A-ACCGCGACCGGAGCCGCGACCGGAG is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 454007. Variant chr11-2884966-A-ACCGCGACCGGAGCCGCGACCGGAG is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 454007. Variant chr11-2884966-A-ACCGCGACCGGAGCCGCGACCGGAG is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 454007. Variant chr11-2884966-A-ACCGCGACCGGAGCCGCGACCGGAG is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 454007. Variant chr11-2884966-A-ACCGCGACCGGAGCCGCGACCGGAG is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 454007. Variant chr11-2884966-A-ACCGCGACCGGAGCCGCGACCGGAG is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 454007. Variant chr11-2884966-A-ACCGCGACCGGAGCCGCGACCGGAG is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 454007. Variant chr11-2884966-A-ACCGCGACCGGAGCCGCGACCGGAG is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 454007.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0000513 (7/136444) while in subpopulation NFE AF = 0.00011 (7/63524). AF 95% confidence interval is 0.0000517. There are 0 homozygotes in GnomAd4. There are 4 alleles in the male GnomAd4 subpopulation. Median coverage is 26. This position passed quality control check.

BS2

High AC in GnomAd4 at 7 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CDKN1C	NM_001122630.2 link	c.467_490dupCTCCGGTCGCGGCTCCGGTCGCGG	p.Ala156_Ala163dup	conservative_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.467_490dupCTCCGGTCGCGGCTCCGGTCGCGG	p.Ala156_Ala163dup	conservative_inframe_insertion	Exon 2 of 4	1	NM_001122630.2	ENSP00000411257.2		P49918-2

Frequencies

GnomAD3 genomes

AF:

0.0000513

AC:

AN:

136444

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:

0.000110

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.0000118

AC:

AN:

845548

Hom.:

Cov.:

AF XY:

0.0000124

AC XY:

AN XY:

404064

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

17868

American (AMR)

AF:

0.00

AC:

AN:

6718

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

11060

East Asian (EAS)

AF:

0.00

AC:

AN:

21360

South Asian (SAS)

AF:

0.00

AC:

AN:

16386

European-Finnish (FIN)

AF:

0.00

AC:

AN:

19856

Middle Eastern (MID)

AF:

0.00

AC:

AN:

2344

European-Non Finnish (NFE)

AF:

0.0000140

AC:

AN:

715692

Other (OTH)

AF:

0.00

AC:

AN:

34264

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

AF:

0.0000513

AC:

AN:

136444

Hom.:

Cov.:

AF XY:

0.0000603

AC XY:

AN XY:

66298

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

35524

American (AMR)

AF:

0.00

AC:

AN:

14234

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3302

East Asian (EAS)

AF:

0.00

AC:

AN:

4460

South Asian (SAS)

AF:

0.00

AC:

AN:

4334

European-Finnish (FIN)

AF:

0.00

AC:

AN:

8072

Middle Eastern (MID)

AF:

0.00

AC:

AN:

266

European-Non Finnish (NFE)

AF:

0.000110

AC:

AN:

63524

Other (OTH)

AF:

0.00

AC:

AN:

1896

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.489

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:2Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

CDKN1C-related disorder

Uncertain:1

Aug 31, 2022

PreventionGenetics, part of Exact Sciences

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The CDKN1C c.500_523dup24 variant is predicted to result in an in-frame duplication (p.Ala167_Ala174dup). To our knowledge, this variant has not been reported in the literature or in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. In ClinVar, this variant is interpreted as likely benign by one submitter (https://www.ncbi.nlm.nih.gov/clinvar/variation/454007). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Beckwith-Wiedemann syndrome;C1846009:IMAGe syndrome

Uncertain:1

Feb 20, 2024

Fulgent Genetics, Fulgent Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Beckwith-Wiedemann syndrome

Benign:1

Jan 19, 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

-0.20

Mutation Taster

=81/19

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