Variant 14-54411661-A-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1PM2

The NM_005192.4(CDKN3):c.371A>G(p.Glu124Gly) variant causes a missense change. The variant allele was found at a frequency of 0.0000167 in 1,613,800 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 Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000039 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000014 ( 0 hom. )

Consequence

CDKN3
NM_005192.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.87

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

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;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CDKN3	NM_005192.4 linkuse as main transcript	c.371A>G	p.Glu124Gly	missense_variant	5/8	ENST00000335183.11	NP_005183.2	Q16667-1
CDKN3	NM_001330173.2 linkuse as main transcript	c.371A>G	p.Glu124Gly	missense_variant	5/9		NP_001317102.1	G3V2J7
CDKN3	NM_001130851.2 linkuse as main transcript	c.251A>G	p.Glu84Gly	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.371A>G	p.Glu124Gly	missense_variant	5/8	1	NM_005192.4	ENSP00000335357.6		Q16667-1

Frequencies

GnomAD3 genomes

AF:

0.0000394

AC:

AN:

152220

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:

0.00115

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

GnomAD3 exomes

AF:

0.000108

AC:

AN:

250928

Hom.:

AF XY:

0.000133

AC XY:

AN XY:

135628

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00147

Gnomad SAS 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:

0.0000144

AC:

AN:

1461580

Hom.:

Cov.:

AF XY:

0.0000138

AC XY:

AN XY:

727098

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000504

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000394

AC:

AN:

152220

Hom.:

Cov.:

AF XY:

0.0000538

AC XY:

AN XY:

74366

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00115

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000869

ExAC

AF:

0.0000988

AC:

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

Feb 28, 2023

The c.371A>G (p.E124G) alteration is located in exon 5 (coding exon 5) of the CDKN3 gene. This alteration results from a A to G substitution at nucleotide position 371, causing the glutamic acid (E) at amino acid position 124 to be replaced by a glycine (G). 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

0.11

BayesDel_addAF

Benign

-0.31

BayesDel_noAF

Benign

-0.24

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.096

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

Eigen

Uncertain

0.37

Eigen_PC

Uncertain

0.40

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.93

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

M_CAP

Benign

0.031

MetaRNN

Benign

0.14

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

MetaSVM

Benign

-0.67

MutationAssessor

Uncertain

2.4

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

PrimateAI

Benign

0.41

PROVEAN

Uncertain

-4.0

.;D;D;D;D;D;D;D

REVEL

Uncertain

0.35

Sift

Uncertain

0.0080

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

Sift4G

Uncertain

0.0080

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

Polyphen

0.97, 0.19

.;D;.;B;.;.;.;.

Vest4

0.56

MutPred

0.66

Gain of catalytic residue at I122 (P = 0.1953);Gain of catalytic residue at I122 (P = 0.1953);Gain of catalytic residue at I122 (P = 0.1953);.;Gain of catalytic residue at I122 (P = 0.1953);Gain of catalytic residue at I122 (P = 0.1953);Gain of catalytic residue at I122 (P = 0.1953);.;

MVP

0.89

MPC

0.93

ClinPred

0.26

GERP RS

6.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.57

gMVP

0.48

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.22

Details are displayed if max score is > 0.2

DS_DL_spliceai

0.22

Position offset: 45

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