14-54399905-A-G

Position:

• chr14-54399905-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM1 PM2 BP4_Moderate

The NM_005192.4(CDKN3):​c.21A>G​(p.Ile7Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000141 in 1,416,998 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: CDKN3 NM_005192.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.667

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 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 2 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
• BP4: Computational evidence support a benign effect (MetaRNN=0.07258716).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CDKN3	NM_005192.4	c.21A>G	p.Ile7Met	missense_variant	2/8	ENST00000335183.11	NP_005183.2
CDKN3	NM_001330173.2	c.21A>G	p.Ile7Met	missense_variant	2/9		NP_001317102.1
CDKN3	NM_001130851.2	c.21A>G	p.Ile7Met	missense_variant	2/7		NP_001124323.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CDKN3	ENST00000335183.11	c.21A>G	p.Ile7Met	missense_variant	2/8	1	NM_005192.4	ENSP00000335357.6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000141 AC: 2 AN: 1416998 Hom.: 0 Cov.: 24 AF XY: 0.00 AC XY: 0 AN XY: 708118

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: 0.00

Gnomad4 OTH exome AF: 0.0000170

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 07, 2023

The c.21A>G (p.I7M) alteration is located in exon 2 (coding exon 2) of the CDKN3 gene. This alteration results from a A to G substitution at nucleotide position 21, causing the isoleucine (I) at amino acid position 7 to be replaced by a methionine (M). 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	0.062
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.60
CADD	Benign	13
DANN	Benign	0.54
DEOGEN2	Benign	0.0018	T;T;.;.;T;.;T;.
Eigen	Benign	-0.54
Eigen_PC	Benign	-0.32
FATHMM_MKL	Benign	0.13	N
LIST_S2	Benign	0.75	T;T;T;T;T;T;T;T
M_CAP	Benign	0.0053	T
MetaRNN	Benign	0.073	T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-1.8	.;N;.;N;.;.;.;.
PrimateAI	Benign	0.42	T
PROVEAN	Benign	0.32	.;N;N;N;N;N;N;.
REVEL	Benign	0.054
Sift	Benign	0.60	.;T;T;T;T;T;T;.
Sift4G	Benign	1.0	T;T;T;D;T;T;T;T
Polyphen		0.0030, 0.0010	.;B;.;B;.;.;.;.
Vest4		0.10
MutPred		0.48		Loss of glycosylation at S6 (P = 0.0492);Loss of glycosylation at S6 (P = 0.0492);Loss of glycosylation at S6 (P = 0.0492);Loss of glycosylation at S6 (P = 0.0492);Loss of glycosylation at S6 (P = 0.0492);Loss of glycosylation at S6 (P = 0.0492);Loss of glycosylation at S6 (P = 0.0492);.;
MVP		0.67
MPC		0.38
ClinPred		0.068	T
GERP RS		3.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.041
gMVP		0.24

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

Other links and lift over

dbSNP: rs1166422319; hg19: chr14-54866623;