11-2884962-C-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_001122630.2(CDKN1C):c.495G>C(p.Ala165Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00731 in 1,050,826 control chromosomes in the GnomAD database, including 39 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. A165A) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0060 ( 9 hom., cov: 32)

Exomes 𝑓: 0.0075 ( 30 hom. )

Consequence

CDKN1C
NM_001122630.2 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: -0.489

Publications

2 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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.69).

BP6

Variant 11-2884962-C-G is Benign according to our data. Variant chr11-2884962-C-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 193041.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.489 with no splicing effect.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00602 (886/147248) while in subpopulation NFE AF = 0.00765 (506/66114). AF 95% confidence interval is 0.0071. There are 9 homozygotes in GnomAd4. There are 465 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 886 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CDKN1C	NM_001122630.2 link	c.495G>C	p.Ala165Ala	synonymous_variant	Exon 2 of 4	ENST00000440480.8	NP_001116102.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CDKN1C	ENST00000440480.8 link	c.495G>C	p.Ala165Ala	synonymous_variant	Exon 2 of 4	1	NM_001122630.2	ENSP00000411257.2

Frequencies

GnomAD3 genomes

AF:

0.00601

AC:

885

AN:

147142

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00141

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00631

Gnomad ASJ

AF:

0.00206

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00506

Gnomad FIN

AF:

0.0207

Gnomad MID

AF:

0.00325

Gnomad NFE

AF:

0.00765

Gnomad OTH

AF:

0.00348

GnomAD2 exomes

AF:

0.0135

AC:

AN:

222

AF XY:

0.0156

show subpopulations

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0140

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00752

AC:

6796

AN:

903578

Hom.:

Cov.:

AF XY:

0.00765

AC XY:

3291

AN XY:

430106

show subpopulations

African (AFR)

AF:

0.000655

AC:

AN:

18328

American (AMR)

AF:

0.00525

AC:

AN:

6478

Ashkenazi Jewish (ASJ)

AF:

0.00226

AC:

AN:

11076

East Asian (EAS)

AF:

0.00

AC:

AN:

20812

South Asian (SAS)

AF:

0.00801

AC:

138

AN:

17220

European-Finnish (FIN)

AF:

0.0204

AC:

394

AN:

19308

Middle Eastern (MID)

AF:

0.00246

AC:

AN:

2438

European-Non Finnish (NFE)

AF:

0.00771

AC:

5956

AN:

772288

Other (OTH)

AF:

0.00648

AC:

231

AN:

35630

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.494

Heterozygous variant carriers

313

626

938

1251

1564

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

264

528

792

1056

1320

<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:

0.00602

AC:

886

AN:

147248

Hom.:

Cov.:

AF XY:

0.00648

AC XY:

465

AN XY:

71806

show subpopulations

African (AFR)

AF:

0.00140

AC:

AN:

40668

American (AMR)

AF:

0.00637

AC:

AN:

14912

Ashkenazi Jewish (ASJ)

AF:

0.00206

AC:

AN:

3406

East Asian (EAS)

AF:

0.00

AC:

AN:

5048

South Asian (SAS)

AF:

0.00506

AC:

AN:

4744

European-Finnish (FIN)

AF:

0.0207

AC:

189

AN:

9150

Middle Eastern (MID)

AF:

0.00352

AC:

AN:

284

European-Non Finnish (NFE)

AF:

0.00765

AC:

506

AN:

66114

Other (OTH)

AF:

0.00344

AC:

AN:

2034

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.491

Heterozygous variant carriers

127

169

211

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome 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

Alfa

AF:

0.00224

Hom.:

Bravo

AF:

0.00480

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

May 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

CDKN1C: BP4, BP7, BS1, BS2 -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

not specified

Benign:3

Mar 27, 2018

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Aug 07, 2020

Genetic Services Laboratory, University of Chicago

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Beckwith-Wiedemann syndrome

Benign:2

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Oct 23, 2020

Sema4, Sema4

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:curation

- -

CDKN1C-related disorder

Benign:1

Sep 13, 2021

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as 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

BayesDel_noAF

Benign

-0.69

CADD

Benign

7.1

(source)

DANN

Benign

0.70

PhyloP100

-0.49

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

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