rs1166422319

Variant names:

• chr14-54399905-A-G
• rs1166422319
• NM_005192.4:c.21A>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. 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. 16/22 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
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.07258716).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005192.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDKN3	NM_005192.4	MANE Select	c.21A>G	p.Ile7Met	missense	Exon 2 of 8	NP_005183.2
	CDKN3	NM_001330173.2		c.21A>G	p.Ile7Met	missense	Exon 2 of 9	NP_001317102.1	G3V2J7
	CDKN3	NM_001130851.2		c.21A>G	p.Ile7Met	missense	Exon 2 of 7	NP_001124323.1	Q16667-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDKN3	ENST00000335183.11	TSL:1 MANE Select	c.21A>G	p.Ile7Met	missense	Exon 2 of 8	ENSP00000335357.6	Q16667-1
	CDKN3	ENST00000442975.6	TSL:1	c.21A>G	p.Ile7Met	missense	Exon 2 of 7	ENSP00000415333.2	Q16667-2
	CDKN3	ENST00000216414.12	TSL:1	n.17A>G		non_coding_transcript_exon	Exon 1 of 4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00 AC: 0 AN: 250366 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS 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: 0.00000141 AC: 2 AN: 1416998 Hom.: 0 Cov.: 24 AF XY: 0.00 AC XY: 0 AN XY: 708118

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 32568

American (AMR) AF: 0.00 AC: 0 AN: 44506

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25882

East Asian (EAS) AF: 0.00 AC: 0 AN: 39364

South Asian (SAS) AF: 0.00 AC: 0 AN: 85296

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53330

Middle Eastern (MID) AF: 0.000177 AC: 1 AN: 5662

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1071516

Other (OTH) AF: 0.0000170 AC: 1 AN: 58874

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0000000000983081), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

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
Eigen	Benign	-0.54
Eigen_PC	Benign	-0.32
FATHMM_MKL	Benign	0.13	N
LIST_S2	Benign	0.75	T
M_CAP	Benign	0.0053	T
MetaRNN	Benign	0.073	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-1.8	N
PhyloP100		0.67
PrimateAI	Benign	0.42	T
PROVEAN	Benign	0.32	N
REVEL	Benign	0.054
Sift	Benign	0.60	T
Sift4G	Benign	1.0	T
Polyphen		0.0030	B
Vest4		0.10
MutPred		0.48		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
Mutation Taster		=87/13	polymorphism

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

Other links and lift over

dbSNP: rs1166422319; hg19: chr14-54866623;