11-125367939-A-G

Variant names:

• chr11-125367939-A-G
• rs201213983
• NM_001382323.2:c.181A>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001382323.2(PKNOX2):​c.181A>G​(p.Ile61Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000171 in 1,461,104 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict 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. I61L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000017 (0 hom.)
• Consequence: PKNOX2 NM_001382323.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.62
• Publications: 0 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.05743912).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001382323.2. 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
	PKNOX2	NM_001382323.2	MANE Select	c.181A>G	p.Ile61Val	missense	Exon 5 of 13	NP_001369252.1	Q96KN3-1
	PKNOX2	NM_001382324.1		c.181A>G	p.Ile61Val	missense	Exon 6 of 14	NP_001369253.1	Q96KN3-1
	PKNOX2	NM_001382325.1		c.181A>G	p.Ile61Val	missense	Exon 4 of 12	NP_001369254.1	Q96KN3-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PKNOX2	ENST00000298282.14	TSL:1 MANE Select	c.181A>G	p.Ile61Val	missense	Exon 5 of 13	ENSP00000298282.8	Q96KN3-1
	PKNOX2	ENST00000878499.1		c.181A>G	p.Ile61Val	missense	Exon 5 of 14	ENSP00000548558.1
	PKNOX2	ENST00000878493.1		c.181A>G	p.Ile61Val	missense	Exon 4 of 12	ENSP00000548552.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.0000171 AC: 25 AN: 1461104 Hom.: 0 Cov.: 31 AF XY: 0.0000165 AC XY: 12 AN XY: 726844

African (AFR) AF: 0.00 AC: 0 AN: 33462

American (AMR) AF: 0.00 AC: 0 AN: 44646

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26120

East Asian (EAS) AF: 0.00 AC: 0 AN: 39616

South Asian (SAS) AF: 0.00 AC: 0 AN: 86148

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53344

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5724

European-Non Finnish (NFE) AF: 0.0000225 AC: 25 AN: 1111682

Other (OTH) AF: 0.00 AC: 0 AN: 60362

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.052
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	12
DANN	Benign	0.80
DEOGEN2	Benign	0.018	T
Eigen	Benign	-0.43
Eigen_PC	Benign	-0.14
FATHMM_MKL	Benign	0.76	D
LIST_S2	Benign	0.61	T
M_CAP	Benign	0.0077	T
MetaRNN	Benign	0.057	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.55	N
PhyloP100		2.6
PrimateAI	Benign	0.41	T
PROVEAN	Benign	0.060	N
REVEL	Benign	0.071
Sift	Benign	0.98	T
Sift4G	Benign	0.66	T
Polyphen		0.0010	B
Vest4		0.18
MutPred		0.19		Loss of catalytic residue at P63 (P = 0.0368)
MVP		0.37
MPC		0.25
ClinPred		0.75	D
GERP RS		5.5
Varity_R		0.045
gMVP		0.13
Mutation Taster		=86/14	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: rs201213983; hg19: chr11-125237835;