14-54420016-C-T

Variant names:

• chr14-54420016-C-T
• rs2030674385
• NM_005192.4:c.577C>T

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1 PM2 PP3

The NM_005192.4(CDKN3):​c.577C>T​(p.Arg193Trp) variant causes a missense change. The variant allele was found at a frequency of 0.00000206 in 1,455,960 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: CDKN3 NM_005192.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.98

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 5 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
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.805

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CDKN3	NM_005192.4	c.577C>T	p.Arg193Trp	missense_variant	Exon 8 of 8	ENST00000335183.11	NP_005183.2
CDKN3	NM_001130851.2	c.457C>T	p.Arg153Trp	missense_variant	Exon 7 of 7		NP_001124323.1
CDKN3	NM_001330173.2	c.*58C>T		3_prime_UTR_variant	Exon 9 of 9		NP_001317102.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CDKN3	ENST00000335183.11	c.577C>T	p.Arg193Trp	missense_variant	Exon 8 of 8	1	NM_005192.4	ENSP00000335357.6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000206 AC: 3 AN: 1455960 Hom.: 0 Cov.: 27 AF XY: 0.00000138 AC XY: 1 AN XY: 724716

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000253

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000181

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Sep 11, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.577C>T (p.R193W) alteration is located in exon 8 (coding exon 8) of the CDKN3 gene. This alteration results from a C to T substitution at nucleotide position 577, causing the arginine (R) at amino acid position 193 to be replaced by a tryptophan (W). 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	Uncertain	0.38
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Uncertain	0.12
CADD	Pathogenic	33
DANN	Uncertain	1.0
DEOGEN2	Benign	0.13	T;T;.;T;T
Eigen	Pathogenic	0.74
Eigen_PC	Pathogenic	0.79
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.96	D;D;D;D;D
M_CAP	Benign	0.017	T
MetaRNN	Pathogenic	0.80	D;D;D;D;D
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.1	.;M;.;.;.
PrimateAI	Uncertain	0.68	T
PROVEAN	Uncertain	-4.0	.;D;D;D;D
REVEL	Uncertain	0.41
Sift	Uncertain	0.0010	.;D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D;D
Polyphen		1.0	.;D;D;.;.
Vest4		0.76
MutPred		0.57		.;Loss of disorder (P = 0.0016);.;.;.;
MVP		0.81
MPC		1.2
ClinPred		1.0	D
GERP RS		6.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.51
gMVP		0.70

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs2030674385; hg19: chr14-54886734; COSMIC: COSV99369887; COSMIC: COSV99369887;