Genetic Variant CDKN1C:p.Pro141Pro (chr11-2885034-C-T) – ACMG Classification: Benign (-14 pts)

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_StrongBP6BP7BS1BS2

The NM_001122630.2(CDKN1C):c.423G>A(p.Pro141Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000487 in 1,312,894 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. P141P) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00043 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00049 ( 0 hom. )

Consequence

CDKN1C
NM_001122630.2 synonymous

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:3

Conservation

PhyloP100: -0.126

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: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P
IMAGe syndrome
Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: G2P, Orphanet, Labcorp Genetics (formerly Invitae), Ambry Genetics, Illumina
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:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -14 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.75).

BP6

Variant 11-2885034-C-T is Benign according to our data. Variant chr11-2885034-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 236952.

BP7

Synonymous conserved (PhyloP=-0.126 with no splicing effect.

BS1

Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00043 (65/151012) while in subpopulation AMR AF = 0.000987 (15/15204). AF 95% confidence interval is 0.000607. There are 0 homozygotes in GnomAd4. There are 27 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High AC in GnomAd4 at 65 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001122630.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CDKN1C	NM_001122630.2	MANE Select	c.423G>A	p.Pro141Pro	synonymous	Exon 2 of 4	NP_001116102.1	P49918-2
CDKN1C	NM_000076.2		c.456G>A	p.Pro152Pro	synonymous	Exon 1 of 3	NP_000067.1	P49918-1
CDKN1C	NM_001362474.2		c.456G>A	p.Pro152Pro	synonymous	Exon 1 of 3	NP_001349403.1	P49918-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CDKN1C	ENST00000440480.8	TSL:1 MANE Select	c.423G>A	p.Pro141Pro	synonymous	Exon 2 of 4	ENSP00000411257.2	P49918-2
CDKN1C	ENST00000414822.8	TSL:1	c.456G>A	p.Pro152Pro	synonymous	Exon 1 of 3	ENSP00000413720.3	P49918-1
CDKN1C	ENST00000430149.3	TSL:1	c.456G>A	p.Pro152Pro	synonymous	Exon 1 of 3	ENSP00000411552.2	P49918-1

Frequencies

GnomAD3 genomes

AF:

0.000431

AC:

AN:

150900

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000486

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000988

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:

0.000680

Gnomad OTH

AF:

0.000969

GnomAD2 exomes

AF:

0.000448

AC:

AN:

2234

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000674

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000494

AC:

574

AN:

1161882

Hom.:

Cov.:

AF XY:

0.000505

AC XY:

283

AN XY:

560738

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

22748

American (AMR)

AF:

0.000687

AC:

AN:

8732

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

15614

East Asian (EAS)

AF:

0.00

AC:

AN:

26592

South Asian (SAS)

AF:

0.0000229

AC:

AN:

43688

European-Finnish (FIN)

AF:

0.0000725

AC:

AN:

27588

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3224

European-Non Finnish (NFE)

AF:

0.000559

AC:

540

AN:

966032

Other (OTH)

AF:

0.000525

AC:

AN:

47664

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.513

Heterozygous variant carriers

126

157

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

120

<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:

0.000430

AC:

AN:

151012

Hom.:

Cov.:

AF XY:

0.000366

AC XY:

AN XY:

73778

show subpopulations

African (AFR)

AF:

0.0000484

AC:

AN:

41302

American (AMR)

AF:

0.000987

AC:

AN:

15204

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3450

East Asian (EAS)

AF:

0.00

AC:

AN:

5114

South Asian (SAS)

AF:

0.00

AC:

AN:

4792

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10250

Middle Eastern (MID)

AF:

0.00

AC:

AN:

290

European-Non Finnish (NFE)

AF:

0.000680

AC:

AN:

67614

Other (OTH)

AF:

0.000958

AC:

AN:

2088

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

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.:

Bravo

AF:

0.000412

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Beckwith-Wiedemann syndrome (2)

CDKN1C-related disorder (1)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.75

CADD

Benign

8.0

(source)

DANN

Benign

0.97

PhyloP100

-0.13

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.3

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over