11-125385715-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_001382323.2(PKNOX2):c.392A>G(p.Asp131Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,322 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: 0.0000014 (0 hom.)
• Consequence: PKNOX2 NM_001382323.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.32

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

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.889

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PKNOX2	NM_001382323.2	c.392A>G	p.Asp131Gly	missense_variant	6/13	ENST00000298282.14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PKNOX2	ENST00000298282.14	c.392A>G	p.Asp131Gly	missense_variant	6/13	1	NM_001382323.2	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461322 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 726936

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: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 13, 2022

The c.392A>G (p.D131G) alteration is located in exon 6 (coding exon 3) of the PKNOX2 gene. This alteration results from a A to G substitution at nucleotide position 392, causing the aspartic acid (D) at amino acid position 131 to be replaced by a glycine (G). 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	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.15
Cadd	Pathogenic	34
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.44	T
Eigen	Uncertain	0.57
Eigen_PC	Uncertain	0.63
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Benign	0.021	T
MetaRNN	Pathogenic	0.89	D
MetaSVM	Benign	-0.72	T
MutationAssessor	Uncertain	2.4	M
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Pathogenic	0.88	D
PROVEAN	Pathogenic	-6.6	D
REVEL	Pathogenic	0.70
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.029	D
Polyphen		1.0	D
Vest4		0.99
MutPred		0.66		Gain of ubiquitination at K136 (P = 0.0913);
MVP		0.86
MPC		0.99
ClinPred		1.0	D
GERP RS		5.5
Varity_R		0.89
gMVP		0.88

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr11-125255611;