NM_002586.5:c.178A>G

Variant names:

• chr6-32189738-T-C
• NM_002586.5:c.178A>G

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_002586.5(PBX2):​c.178A>G​(p.Ile60Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000686 in 1,457,316 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: PBX2 NM_002586.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.65
• Publications: 0 publications found

Genes affected

PBX2 (HGNC:8633): (PBX homeobox 2) This gene encodes a ubiquitously expressed member of the TALE/PBX homeobox family. It was identified by its similarity to a homeobox gene which is involved in t(1;19) translocation in acute pre-B-cell leukemias. This protein is a transcriptional activator which binds to the TLX1 promoter. The gene is located within the major histocompatibility complex (MHC) on chromosome 6. [provided by RefSeq, Jul 2008]

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002586.5. 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
	PBX2	NM_002586.5	MANE Select	c.178A>G	p.Ile60Val	missense	Exon 1 of 9	NP_002577.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PBX2	ENST00000375050.6	TSL:1 MANE Select	c.178A>G	p.Ile60Val	missense	Exon 1 of 9	ENSP00000364190.3	P40425
	PBX2	ENST00000478678.5	TSL:1	n.205A>G		non_coding_transcript_exon	Exon 1 of 6

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 6.86e-7 AC: 1 AN: 1457316 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 724988

African (AFR) AF: 0.00 AC: 0 AN: 33086

American (AMR) AF: 0.00 AC: 0 AN: 44538

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25960

East Asian (EAS) AF: 0.00 AC: 0 AN: 39022

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86138

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52370

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5718

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1110254

Other (OTH) AF: 0.00 AC: 0 AN: 60230

GnomAD4 genome Cov.: 31

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.94
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.47
CADD	Pathogenic	32
DANN	Uncertain	0.99
DEOGEN2	Benign	0.10	T
Eigen	Uncertain	0.31
Eigen_PC	Uncertain	0.33
FATHMM_MKL	Uncertain	0.96	D
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.26	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.8	M
PhyloP100		2.6
PrimateAI	Pathogenic	0.85	D
PROVEAN	Benign	-0.71	N
REVEL	Benign	0.13
Sift	Benign	0.34	T
Sift4G	Benign	0.47	T
Polyphen		0.99	D
Vest4		0.32
MutPred		0.39		Loss of helix (P = 0.0444)
MVP		0.40
MPC		1.6
ClinPred		0.97	D
GERP RS		3.9
PromoterAI		-0.054	Neutral
Varity_R		0.083
gMVP		0.65
Mutation Taster		=66/34	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.35		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.35		Position offset: 1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

hg19: chr6-32157515;