Variant chr21-43016959-C-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2

The NM_004571.5(PKNOX1):c.574C>G(p.Pro192Ala) variant causes a missense change. The variant allele was found at a frequency of 0.0000205 in 1,612,732 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000021 ( 0 hom. )

Consequence

PKNOX1
NM_004571.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.84

Variant links:

Genes affected

PKNOX1 (HGNC:9022): (PBX/knotted 1 homeobox 1) Enables sequence-specific double-stranded DNA binding activity. Predicted to be involved in angiogenesis and regulation of transcription by RNA polymerase II. Predicted to act upstream of or within camera-type eye development; hemopoiesis; and positive regulation of transcription by RNA polymerase II. Predicted to be located in cytoplasm and nucleus. Predicted to be part of chromatin. [provided by Alliance of Genome Resources, Apr 2022]

PKNOX1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -4 ACMG points.

BS2

High AC in GnomAdExome4 at 31 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PKNOX1	NM_004571.5 linkuse as main transcript	c.574C>G	p.Pro192Ala	missense_variant	6/11	ENST00000291547.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PKNOX1	ENST00000291547.10 linkuse as main transcript	c.574C>G	p.Pro192Ala	missense_variant	6/11	1	NM_004571.5	P1	P55347-1
PKNOX1	ENST00000432907.6 linkuse as main transcript	c.223C>G	p.Pro75Ala	missense_variant	5/10	2
PKNOX1	ENST00000480179.1 linkuse as main transcript	n.633C>G		non_coding_transcript_exon_variant	6/6	2
PKNOX1	ENST00000560448.5 linkuse as main transcript	c.*216C>G		3_prime_UTR_variant, NMD_transcript_variant	4/9	5

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152192

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:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000200

AC:

AN:

249968

Hom.:

AF XY:

0.0000296

AC XY:

AN XY:

135230

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000289

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:

0.0000353

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000212

AC:

AN:

1460540

Hom.:

Cov.:

AF XY:

0.0000234

AC XY:

AN XY:

726524

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000224

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:

0.0000270

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152192

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74364

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000151

ExAC

AF:

0.0000330

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

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

Dec 28, 2022

The c.574C>G (p.P192A) alteration is located in exon 6 (coding exon 5) of the PKNOX1 gene. This alteration results from a C to G substitution at nucleotide position 574, causing the proline (P) at amino acid position 192 to be replaced by an alanine (A). 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

0.18

BayesDel_addAF

Uncertain

0.14

BayesDel_noAF

Uncertain

0.070

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.59

D;.

Eigen

Uncertain

0.50

Eigen_PC

Uncertain

0.46

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.91

D;D

M_CAP

Benign

0.039

MetaRNN

Uncertain

0.64

D;D

MetaSVM

Uncertain

0.26

MutationAssessor

Benign

2.0

M;.

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Uncertain

0.77

PROVEAN

Uncertain

-3.1

D;D

REVEL

Uncertain

0.61

Sift

Benign

0.064

T;T

Sift4G

Benign

0.16

T;T

Polyphen

0.97

D;.

Vest4

0.64

MutPred

0.44

Loss of sheet (P = 0.0457);.;

MVP

0.69

MPC

0.34

ClinPred

0.54

GERP RS

5.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.11

gMVP

0.53

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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.

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