11-2884966-ACCGCGACCGGAGCCGCGACCGGAG-ACCGCGACCGGAGCCGCGACCGGAGCCGCGACCGGAG

Variant names:

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_StrongBS1BS2

The NM_001122630.2(CDKN1C):c.479_490dupCTCCGGTCGCGG(p.Ala160_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 0.0000794 in 982,068 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 Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. V164V) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00034 ( 0 hom., cov: 26)

Exomes 𝑓: 0.000037 ( 0 hom. )

Consequence

CDKN1C
NM_001122630.2 conservative_inframe_insertion

Scores

Not classified

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:6

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 -16 ACMG points.

BP6

Variant 11-2884966-A-ACCGCGACCGGAG is Benign according to our data. Variant chr11-2884966-A-ACCGCGACCGGAG is described in CliVar as Likely_benign. Clinvar id is 454008.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-2884966-A-ACCGCGACCGGAG is described in CliVar as Likely_benign. Clinvar id is 454008.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-2884966-A-ACCGCGACCGGAG is described in CliVar as Likely_benign. Clinvar id is 454008.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-2884966-A-ACCGCGACCGGAG is described in CliVar as Likely_benign. Clinvar id is 454008.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-2884966-A-ACCGCGACCGGAG is described in CliVar as Likely_benign. Clinvar id is 454008.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-2884966-A-ACCGCGACCGGAG is described in CliVar as Likely_benign. Clinvar id is 454008.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-2884966-A-ACCGCGACCGGAG is described in CliVar as Likely_benign. Clinvar id is 454008.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-2884966-A-ACCGCGACCGGAG is described in CliVar as Likely_benign. Clinvar id is 454008.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-2884966-A-ACCGCGACCGGAG is described in CliVar as Likely_benign. Clinvar id is 454008.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-2884966-A-ACCGCGACCGGAG is described in CliVar as Likely_benign. Clinvar id is 454008.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-2884966-A-ACCGCGACCGGAG is described in CliVar as Likely_benign. Clinvar id is 454008.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-2884966-A-ACCGCGACCGGAG is described in CliVar as Likely_benign. Clinvar id is 454008.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-2884966-A-ACCGCGACCGGAG is described in CliVar as Likely_benign. Clinvar id is 454008.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.000344 (47/136524) while in subpopulation AMR AF = 0.00175 (25/14258). AF 95% confidence interval is 0.00122. There are 0 homozygotes in GnomAd4. There are 27 alleles in the male GnomAd4 subpopulation. Median coverage is 26. This position passed quality control check.

BS2

High AC in GnomAd4 at 47 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CDKN1C	NM_001122630.2 link	c.479_490dupCTCCGGTCGCGG	p.Ala160_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.479_490dupCTCCGGTCGCGG	p.Ala160_Ala163dup	conservative_inframe_insertion	Exon 2 of 4	1	NM_001122630.2	ENSP00000411257.2		P49918-2

Frequencies

GnomAD3 genomes

AF:

0.000344

AC:

AN:

136444

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000450

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00176

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000224

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00376

Gnomad NFE

AF:

0.0000472

Gnomad OTH

AF:

0.000527

GnomAD4 exome

AF:

0.0000367

AC:

AN:

845544

Hom.:

Cov.:

AF XY:

0.0000346

AC XY:

AN XY:

404060

show subpopulations

African (AFR)

AF:

0.000112

AC:

AN:

17868

American (AMR)

AF:

0.00119

AC:

AN:

6718

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

11060

East Asian (EAS)

AF:

0.0000468

AC:

AN:

21360

South Asian (SAS)

AF:

0.0000610

AC:

AN:

16384

European-Finnish (FIN)

AF:

0.00

AC:

AN:

19856

Middle Eastern (MID)

AF:

0.00

AC:

AN:

2344

European-Non Finnish (NFE)

AF:

0.0000224

AC:

AN:

715690

Other (OTH)

AF:

0.0000876

AC:

AN:

34264

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.488

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:

0.000344

AC:

AN:

136524

Hom.:

Cov.:

AF XY:

0.000407

AC XY:

AN XY:

66388

show subpopulations

African (AFR)

AF:

0.000449

AC:

AN:

35616

American (AMR)

AF:

0.00175

AC:

AN:

14258

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3302

East Asian (EAS)

AF:

0.000225

AC:

AN:

4446

South Asian (SAS)

AF:

0.00

AC:

AN:

4330

European-Finnish (FIN)

AF:

0.00

AC:

AN:

8072

Middle Eastern (MID)

AF:

0.00410

AC:

AN:

244

European-Non Finnish (NFE)

AF:

0.0000472

AC:

AN:

63512

Other (OTH)

AF:

0.000523

AC:

AN:

1912

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

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: Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Beckwith-Wiedemann syndrome

Benign:2

Jan 13, 2021

Sema4, Sema4

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:curation

- -

Feb 01, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:1

Feb 16, 2025

Laboratory of Genetics, Children's Clinical University Hospital Latvia

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

CDKN1C-related disorder

Benign:1

Sep 17, 2024

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). -

Inborn genetic diseases

Benign:1

Aug 18, 2022

Ambry Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

not provided

Benign:1

Mar 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

CDKN1C: BS1 -

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