Genetic Variant CDKN1C:p.Leu227Ile (chr11-2884778-G-T) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

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

The NM_001122630.2(CDKN1C):c.679C>A(p.Leu227Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000074 in 1,352,004 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L227F) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 7.4e-7 ( 0 hom. )

Consequence

CDKN1C
NM_001122630.2 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.118

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:

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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=0.13749492).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CDKN1C	NM_001122630.2 link	c.679C>A	p.Leu227Ile	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.679C>A	p.Leu227Ile	missense_variant	Exon 2 of 4	1	NM_001122630.2	ENSP00000411257.2		P49918-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.40e-7

AC:

AN:

1352004

Hom.:

Cov.:

AF XY:

0.00000149

AC XY:

AN XY:

672288

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:

27936

American (AMR)

AF:

0.00

AC:

AN:

35888

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

23108

East Asian (EAS)

AF:

0.00

AC:

AN:

30562

South Asian (SAS)

AF:

0.00

AC:

AN:

78760

European-Finnish (FIN)

AF:

0.00

AC:

AN:

35138

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5056

European-Non Finnish (NFE)

AF:

9.43e-7

AC:

AN:

1060794

Other (OTH)

AF:

0.00

AC:

AN:

54762

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 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: 0.225

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.094

BayesDel_noAF

Benign

-0.37

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.047

T;T;.

Eigen

Benign

-0.95

Eigen_PC

Benign

-0.99

FATHMM_MKL

Benign

0.014

LIST_S2

Benign

0.27

.;T;T

M_CAP

Pathogenic

0.93

MetaRNN

Benign

0.14

T;T;T

MetaSVM

Benign

-0.55

MutationAssessor

Benign

0.34

N;N;.

PhyloP100

-0.12

PrimateAI

Pathogenic

0.85

PROVEAN

Benign

-0.37

N;N;N

REVEL

Benign

0.092

Sift

Benign

0.088

T;T;T

Sift4G

Benign

0.52

T;T;T

Polyphen

0.061

B;B;.

Vest4

0.10

MutPred

0.19

Loss of glycosylation at P237 (P = 0.1045);Loss of glycosylation at P237 (P = 0.1045);.;

MVP

0.43

MPC

1.4

ClinPred

0.089

GERP RS

0.45

Varity_R

0.097

gMVP

0.050

Mutation Taster

=93/7

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over