11-125410199-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001382323.2(PKNOX2):​c.592C>T​(p.Leu198Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000267 in 1,461,752 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 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: 0.000027 ( 0 hom. )

Consequence

PKNOX2
NM_001382323.2 missense

Scores

2
17

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.45
Variant links:
Genes affected
PKNOX2 (HGNC:16714): (PBX/knotted 1 homeobox 2) Homeodomain proteins are sequence-specific transcription factors that share a highly conserved DNA-binding domain and play fundamental roles in cell proliferation, differentiation, and death. PKNOX2 belongs to the TALE (3-amino acid loop extension) class of homeodomain proteins characterized by a 3-amino acid extension between alpha helices 1 and 2 within the homeodomain (Imoto et al., 2001 [PubMed 11549286]).[supplied by OMIM, Oct 2009]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.12154037).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
PKNOX2NM_001382323.2 linkc.592C>T p.Leu198Phe missense_variant Exon 8 of 13 ENST00000298282.14 NP_001369252.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
PKNOX2ENST00000298282.14 linkc.592C>T p.Leu198Phe missense_variant Exon 8 of 13 1 NM_001382323.2 ENSP00000298282.8 Q96KN3-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD3 exomes
AF:
0.00000401
AC:
1
AN:
249380
Hom.:
0
AF XY:
0.00
AC XY:
0
AN XY:
135290
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00000884
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000267
AC:
39
AN:
1461752
Hom.:
0
Cov.:
32
AF XY:
0.0000303
AC XY:
22
AN XY:
727180
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:
0.0000342
Gnomad4 OTH exome
AF:
0.0000166
GnomAD4 genome
Cov.:
32
Alfa
AF:
0.0000936
Hom.:
0
Bravo
AF:
0.0000113
ExAC
AF:
0.00000826
AC:
1
EpiCase
AF:
0.00
EpiControl
AF:
0.0000593

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Feb 01, 2025
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.592C>T (p.L198F) alteration is located in exon 8 (coding exon 5) of the PKNOX2 gene. This alteration results from a C to T substitution at nucleotide position 592, causing the leucine (L) at amino acid position 198 to be replaced by a phenylalanine (F). 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
0.076
BayesDel_addAF
Benign
-0.033
T
BayesDel_noAF
Benign
-0.28
CADD
Uncertain
23
DANN
Uncertain
0.99
DEOGEN2
Benign
0.017
T
Eigen
Benign
-0.34
Eigen_PC
Benign
-0.11
FATHMM_MKL
Benign
0.73
D
LIST_S2
Benign
0.83
T
M_CAP
Benign
0.018
T
MetaRNN
Benign
0.12
T
MetaSVM
Benign
-0.74
T
MutationAssessor
Benign
1.0
L
PrimateAI
Uncertain
0.69
T
PROVEAN
Benign
-0.090
N
REVEL
Benign
0.17
Sift
Benign
0.41
T
Sift4G
Benign
0.71
T
Polyphen
0.0010
B
Vest4
0.42
MutPred
0.23
Loss of phosphorylation at S202 (P = 0.1711);
MVP
0.29
MPC
0.34
ClinPred
0.34
T
GERP RS
4.8
Varity_R
0.070
gMVP
0.31

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.10
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.

Other links and lift over

dbSNP: rs778017645; hg19: chr11-125280095; COSMIC: COSV100021303; API