rs1281835164

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2BP4_StrongBP6

The NM_001122630.2(CDKN1C):c.553G>C(p.Ala185Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000149 in 134,462 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A185L) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000015 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000042 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

CDKN1C
NM_001122630.2 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: -1.18

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.06399709).

BP6

Variant 11-2884904-C-G is Benign according to our data. Variant chr11-2884904-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 524686.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CDKN1C	NM_001122630.2 linkuse as main transcript	c.553G>C	p.Ala185Pro	missense_variant	2/4	ENST00000440480.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CDKN1C	ENST00000440480.8 linkuse as main transcript	c.553G>C	p.Ala185Pro	missense_variant	2/4	1	NM_001122630.2	A2	P49918-2

Frequencies

GnomAD3 genomes

AF:

0.0000149

AC:

AN:

134462

Hom.:

Cov.:

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:

0.000220

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000162

Gnomad OTH

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00000424

AC:

AN:

708232

Hom.:

Cov.:

AF XY:

0.00000300

AC XY:

AN XY:

333274

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000472

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000149

AC:

AN:

134462

Hom.:

Cov.:

AF XY:

0.0000153

AC XY:

AN XY:

65262

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000220

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000162

Gnomad4 OTH

AF:

0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Beckwith-Wiedemann syndrome;C1846009:IMAGe syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Mar 14, 2022

- -

Beckwith-Wiedemann syndrome

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Oct 13, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.060

BayesDel_addAF

Benign

-0.29

BayesDel_noAF

Benign

-0.65

Cadd

Benign

0.96

Dann

Benign

0.61

DEOGEN2

Benign

0.036

T;T;.

Eigen

Benign

-1.4

Eigen_PC

Benign

-1.5

FATHMM_MKL

Benign

0.011

M_CAP

Benign

0.0042

MetaRNN

Benign

0.064

T;T;T

MetaSVM

Benign

-0.98

MutationAssessor

Benign

0.55

N;N;.

MutationTaster

Benign

1.0

N;N;N;N;N

PrimateAI

Uncertain

0.68

PROVEAN

Benign

-0.39

N;N;N

REVEL

Benign

0.014

Sift

Benign

0.22

T;T;T

Sift4G

Benign

1.0

T;T;T

Polyphen

0.030

B;B;.

Vest4

0.092

MutPred

0.32

Gain of relative solvent accessibility (P = 0.0215);Gain of relative solvent accessibility (P = 0.0215);.;

MVP

0.39

MPC

1.6

ClinPred

0.043

GERP RS

-2.7

Varity_R

0.050

gMVP

0.070

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over