11-2884859-C-T

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001122630.2(CDKN1C):c.598G>A(p.Ala200Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000721 in 138,768 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A200S) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0000072 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000023 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

CDKN1C
NM_001122630.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.802

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

CDKN1C links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.10417259).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CDKN1C	NM_001122630.2 link	c.598G>A	p.Ala200Thr	missense_variant	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.598G>A	p.Ala200Thr	missense_variant	Exon 2 of 4	1	NM_001122630.2	ENSP00000411257.2		P49918-2

Frequencies

GnomAD3 genomes

AF:

0.00000721

AC:

AN:

138768

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000263

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00000225

AC:

AN:

887678

Hom.:

Cov.:

AF XY:

0.00000239

AC XY:

AN XY:

418132

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

17254

American (AMR)

AF:

0.00

AC:

AN:

3598

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

8316

East Asian (EAS)

AF:

0.00

AC:

AN:

13976

South Asian (SAS)

AF:

0.0000559

AC:

AN:

17896

European-Finnish (FIN)

AF:

0.00

AC:

AN:

9950

Middle Eastern (MID)

AF:

0.00

AC:

AN:

2108

European-Non Finnish (NFE)

AF:

0.00000128

AC:

AN:

782936

Other (OTH)

AF:

0.00

AC:

AN:

31644

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000081), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.300

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:

0.00000721

AC:

AN:

138768

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

67600

show subpopulations

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.0000263

AC:

AN:

38070

American (AMR)

AF:

0.00

AC:

AN:

14164

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3296

East Asian (EAS)

AF:

0.00

AC:

AN:

4508

South Asian (SAS)

AF:

0.00

AC:

AN:

4150

European-Finnish (FIN)

AF:

0.00

AC:

AN:

7852

Middle Eastern (MID)

AF:

0.00

AC:

AN:

284

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

63700

Other (OTH)

AF:

0.00

AC:

AN:

1906

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.375

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:

0.0000843

Hom.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Beckwith-Wiedemann syndrome

Uncertain:1

Dec 14, 2020

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces alanine with threonine at codon 211 of the CDKN1C protein (p.Ala211Thr). The alanine residue is weakly conserved and there is a small physicochemical difference between alanine and threonine. While this variant is not present in population databases, the frequency information is unreliable, as metrics indicate poor data quality at this position in the ExAC database. This variant has not been reported in the literature in individuals with a CDKN1C-related disease. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). In summary, this variant is a novel missense change with uncertain impact on protein function. It has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.095

BayesDel_addAF

Benign

-0.24

BayesDel_noAF

Benign

-0.58

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.043

T;T;.

Eigen

Benign

-0.85

Eigen_PC

Benign

-0.98

FATHMM_MKL

Benign

0.030

LIST_S2

Uncertain

0.90

.;D;D

M_CAP

Benign

0.059

MetaRNN

Benign

0.10

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.81

L;L;.

PhyloP100

0.80

PrimateAI

Uncertain

0.72

PROVEAN

Benign

-0.17

N;N;N

REVEL

Benign

0.065

Sift

Benign

0.15

T;T;T

Sift4G

Uncertain

0.024

D;D;D

Polyphen

0.89

P;P;.

Vest4

0.10

MutPred

0.28

Gain of glycosylation at A211 (P = 0);Gain of glycosylation at A211 (P = 0);.;

MVP

0.58

MPC

1.2

ClinPred

0.13

GERP RS

-0.36

Varity_R

0.051

gMVP

0.054

Mutation Taster

=99/1

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