11-125351364-C-G

Variant names:

• chr11-125351364-C-G
• rs371091100
• NM_001382323.2:c.59C>G

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001382323.2(PKNOX2):​c.59C>G​(p.Pro20Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00000138 in 1,453,568 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P20L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: PKNOX2 NM_001382323.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.67
• Publications: 1 publications found

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]

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.27741355).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PKNOX2	NM_001382323.2	c.59C>G	p.Pro20Arg	missense_variant	Exon 4 of 13	ENST00000298282.14	NP_001369252.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PKNOX2	ENST00000298282.14	c.59C>G	p.Pro20Arg	missense_variant	Exon 4 of 13	1	NM_001382323.2	ENSP00000298282.8

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000417 AC: 1 AN: 239704 AF XY: 0.00000766

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000296

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: 0.00000138 AC: 2 AN: 1453568 Hom.: 0 Cov.: 30 AF XY: 0.00000277 AC XY: 2 AN XY: 723012

African (AFR) AF: 0.00 AC: 0 AN: 33362

American (AMR) AF: 0.0000225 AC: 1 AN: 44380

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26016

East Asian (EAS) AF: 0.00 AC: 0 AN: 39480

South Asian (SAS) AF: 0.00 AC: 0 AN: 85360

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52906

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5758

European-Non Finnish (NFE) AF: 9.04e-7 AC: 1 AN: 1106272

Other (OTH) AF: 0.00 AC: 0 AN: 60034

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.33
BayesDel_addAF	Uncertain	0.031	T
BayesDel_noAF	Benign	-0.11
CADD	Pathogenic	27
DANN	Benign	0.97
DEOGEN2	Benign	0.037	T;.;.;T
Eigen	Benign	-0.027
Eigen_PC	Benign	0.20
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.85	T;D;D;T
M_CAP	Benign	0.066	D
MetaRNN	Benign	0.28	T;T;T;T
MetaSVM	Benign	-0.43	T
MutationAssessor	Benign	1.4	L;.;.;.
PhyloP100		5.7
PrimateAI	Uncertain	0.78	T
PROVEAN	Benign	-1.0	N;D;D;N
REVEL	Benign	0.28
Sift	Uncertain	0.0030	D;D;D;D
Sift4G	Uncertain	0.010	D;D;D;D
Polyphen		1.0	D;.;.;.
Vest4		0.79
MutPred		0.23		Loss of glycosylation at P20 (P = 0.0119);Loss of glycosylation at P20 (P = 0.0119);Loss of glycosylation at P20 (P = 0.0119);Loss of glycosylation at P20 (P = 0.0119);
MVP		0.51
MPC		0.97
ClinPred		0.68	D
GERP RS		5.6
Varity_R		0.27
gMVP		0.53
Mutation Taster		=45/55	disease causing

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

Other links and lift over

dbSNP: rs371091100; hg19: chr11-125221260;