14-54411563-C-G

Position:

chr14-54411563-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 6P and 1B. PS1_ModeratePM1PM2BP4

The NM_005192.4(CDKN3):c.273C>G(p.Asn91Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000471 in 1,613,960 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 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 nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin UniProt.

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000049 ( 0 hom. )

Consequence

CDKN3
NM_005192.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.37

Variant links:

Genes affected

CDKN3 (HGNC:1791): (cyclin dependent kinase inhibitor 3) The protein encoded by this gene belongs to the dual specificity protein phosphatase family. It was identified as a cyclin-dependent kinase inhibitor, and has been shown to interact with, and dephosphorylate CDK2 kinase, thus prevent the activation of CDK2 kinase. This gene was reported to be deleted, mutated, or overexpressed in several kinds of cancers. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Aug 2008]

CDKN3 links:

CDKN3 (HGNC:):

CDKN3 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 5 ACMG points.

PS1

Transcript NM_005192.4 (CDKN3) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in UniProt

PM1

In a chain Cyclin-dependent kinase inhibitor 3 (size 211) in uniprot entity CDKN3_HUMAN there are 9 pathogenic changes around while only 1 benign (90%) in NM_005192.4

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.3543275).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CDKN3	NM_005192.4 linkuse as main transcript	c.273C>G	p.Asn91Lys	missense_variant	5/8	ENST00000335183.11	NP_005183.2	Q16667-1
CDKN3	NM_001330173.2 linkuse as main transcript	c.273C>G	p.Asn91Lys	missense_variant	5/9		NP_001317102.1	G3V2J7
CDKN3	NM_001130851.2 linkuse as main transcript	c.153C>G	p.Asn51Lys	missense_variant	4/7		NP_001124323.1	Q16667-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CDKN3	ENST00000335183.11 linkuse as main transcript	c.273C>G	p.Asn91Lys	missense_variant	5/8	1	NM_005192.4	ENSP00000335357.6		Q16667-1

Frequencies

GnomAD3 genomes

AF:

0.0000329

AC:

AN:

152188

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

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:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000239

AC:

AN:

251304

Hom.:

AF XY:

0.0000294

AC XY:

AN XY:

135826

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000440

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000486

AC:

AN:

1461772

Hom.:

Cov.:

AF XY:

0.0000495

AC XY:

AN XY:

727204

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:

0.0000576

Gnomad4 OTH exome

AF:

0.000116

GnomAD4 genome

AF:

0.0000329

AC:

AN:

152188

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74352

show subpopulations

Gnomad4 AFR

AF:

0.0000483

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000441

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000900

Hom.:

Bravo

AF:

0.0000378

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ExAC

AF:

0.0000247

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 04, 2024

The c.273C>G (p.N91K) alteration is located in exon 5 (coding exon 5) of the CDKN3 gene. This alteration results from a C to G substitution at nucleotide position 273, causing the asparagine (N) at amino acid position 91 to be replaced by a lysine (K). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.23

BayesDel_addAF

Benign

-0.29

BayesDel_noAF

Benign

-0.47

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.029

T;T;.;.;T;.;D;T

Eigen

Benign

0.016

Eigen_PC

Benign

0.080

FATHMM_MKL

Uncertain

0.91

LIST_S2

Uncertain

0.95

D;D;D;D;D;D;D;D

M_CAP

Benign

0.012

MetaRNN

Benign

0.35

T;T;T;T;T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Uncertain

2.1

.;M;.;.;.;.;.;.

PrimateAI

Uncertain

0.54

PROVEAN

Benign

-1.9

.;N;N;N;N;N;N;N

REVEL

Benign

0.083

Sift

Benign

0.15

.;T;T;T;T;T;T;T

Sift4G

Benign

0.33

T;T;T;T;T;T;T;T

Polyphen

0.90, 0.51

.;P;.;P;.;.;.;.

Vest4

0.54

MutPred

0.57

Gain of methylation at N91 (P = 0.0333);Gain of methylation at N91 (P = 0.0333);Gain of methylation at N91 (P = 0.0333);.;Gain of methylation at N91 (P = 0.0333);Gain of methylation at N91 (P = 0.0333);Gain of methylation at N91 (P = 0.0333);.;

MVP

0.82

MPC

0.45

ClinPred

0.10

GERP RS

3.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.36

gMVP

0.46

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