11-2884022-C-T

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 2P and 11B. PM2BP4_ModerateBP6_Very_StrongBP7

The NM_001122630.2(CDKN1C):​c.900G>A​(p.Pro300Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000193 in 1,558,268 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 Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. P300P) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)
Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

CDKN1C
NM_001122630.2 synonymous

Scores

3
3
10

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 0.270

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

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -9 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.2602449).
BP6
Variant 11-2884022-C-T is Benign according to our data. Variant chr11-2884022-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 705851.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BP7
Synonymous conserved (PhyloP=0.27 with no splicing effect.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
CDKN1CNM_001122630.2 linkc.900G>A p.Pro300Pro synonymous_variant Exon 3 of 4 ENST00000440480.8 NP_001116102.1 P49918-2

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
CDKN1CENST00000440480.8 linkc.900G>A p.Pro300Pro synonymous_variant Exon 3 of 4 1 NM_001122630.2 ENSP00000411257.2 P49918-2

Frequencies

GnomAD3 genomes
AF:
0.00000657
AC:
1
AN:
152098
Hom.:
0
Cov.:
33
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:
0.00316
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD2 exomes
AF:
0.00
AC:
0
AN:
157318
AF XY:
0.00
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:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000142
AC:
2
AN:
1406054
Hom.:
0
Cov.:
32
AF XY:
0.00000144
AC XY:
1
AN XY:
694682
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
32210
American (AMR)
AF:
0.00
AC:
0
AN:
37060
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
25214
East Asian (EAS)
AF:
0.00
AC:
0
AN:
36834
South Asian (SAS)
AF:
0.0000125
AC:
1
AN:
80168
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
46804
Middle Eastern (MID)
AF:
0.000181
AC:
1
AN:
5540
European-Non Finnish (NFE)
AF:
0.00
AC:
0
AN:
1083976
Other (OTH)
AF:
0.00
AC:
0
AN:
58248
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.475
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
2
4
6
8
10
<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:
0.00000657
AC:
1
AN:
152214
Hom.:
0
Cov.:
33
AF XY:
0.00
AC XY:
0
AN XY:
74410
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
41556
American (AMR)
AF:
0.00
AC:
0
AN:
15312
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3464
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5144
South Asian (SAS)
AF:
0.00
AC:
0
AN:
4830
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
10596
Middle Eastern (MID)
AF:
0.00340
AC:
1
AN:
294
European-Non Finnish (NFE)
AF:
0.00
AC:
0
AN:
67990
Other (OTH)
AF:
0.00
AC:
0
AN:
2116
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.475
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

ClinVar

Significance: Likely benign
Submissions summary: Benign:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Beckwith-Wiedemann syndrome Benign:1
Feb 29, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

not provided Benign:1
-
Breakthrough Genomics, Breakthrough Genomics
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:not provided

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.22
D
BayesDel_noAF
Uncertain
0.070
CADD
Benign
14
DANN
Uncertain
0.99
DEOGEN2
Benign
0.020
T;.
Eigen
Benign
-0.28
Eigen_PC
Benign
-0.23
FATHMM_MKL
Benign
0.55
D
LIST_S2
Benign
0.57
.;T
M_CAP
Pathogenic
0.95
D
MetaRNN
Benign
0.26
T;T
MetaSVM
Benign
-0.58
T
PhyloP100
0.27
PROVEAN
Benign
-0.84
N;.
REVEL
Benign
0.14
Sift
Pathogenic
0.0
D;.
Sift4G
Uncertain
0.026
D;.
Polyphen
0.29
B;.
Vest4
0.28
MutPred
0.23
Loss of glycosylation at P122 (P = 0.0464);Loss of glycosylation at P122 (P = 0.0464);
MVP
0.49
ClinPred
0.86
D
GERP RS
1.6
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.8
Mutation Taster
=94/6
polymorphism

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

Other links and lift over

dbSNP: rs1364915876; hg19: chr11-2905252; API