Genetic Variant NM_002145.4:c.682C>T (chr17-48543457-G-A) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_002145.4(HOXB2):c.682C>T(p.Pro228Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000687 in 1,454,762 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 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. P228A) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

HOXB2
NM_002145.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.758

Publications

0 publications found

Variant links:

Genes affected

HOXB2 (HGNC:5113): (homeobox B2) This gene is a member of the Antp homeobox family and encodes a nuclear protein with a homeobox DNA-binding domain. It is included in a cluster of homeobox B genes located on chromosome 17. The encoded protein functions as a sequence-specific transcription factor that is involved in development. Increased expression of this gene is associated with pancreatic cancer. [provided by RefSeq, Jul 2008]

HOXB2 links:

HOXB-AS1 (HGNC:43744): (HOXB cluster antisense RNA 1)

HOXB-AS1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.07853258).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002145.4. 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
	HOXB2	NM_002145.4	MANE Select	c.682C>T	p.Pro228Ser	missense	Exon 2 of 2	NP_002136.1	P14652

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
HOXB2	ENST00000330070.6	TSL:1 MANE Select	c.682C>T	p.Pro228Ser	missense	Exon 2 of 2	ENSP00000331741.4	P14652
HOXB-AS1	ENST00000504972.4	TSL:3	n.144G>A		non_coding_transcript_exon	Exon 1 of 2
HOXB2	ENST00000571287.1	TSL:3	n.327C>T		non_coding_transcript_exon	Exon 2 of 2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.87e-7

AC:

AN:

1454762

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

723450

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33260

American (AMR)

AF:

0.00

AC:

AN:

44192

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25970

East Asian (EAS)

AF:

0.00

AC:

AN:

39516

South Asian (SAS)

AF:

0.00

AC:

AN:

86016

European-Finnish (FIN)

AF:

0.00

AC:

AN:

50382

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5570

European-Non Finnish (NFE)

AF:

9.01e-7

AC:

AN:

1109872

Other (OTH)

AF:

0.00

AC:

AN:

59984

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.575

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.078

BayesDel_addAF

Benign

-0.15

BayesDel_noAF

Benign

-0.45

CADD

Benign

2.6

(source)

DANN

Benign

0.85

DEOGEN2

Benign

0.080

Eigen

Benign

-1.0

Eigen_PC

Benign

-0.96

FATHMM_MKL

Benign

0.27

LIST_S2

Benign

0.50

M_CAP

Pathogenic

0.37

MetaRNN

Benign

0.079

MetaSVM

Benign

-0.63

MutationAssessor

Benign

1.7

PhyloP100

-0.76

PrimateAI

Uncertain

0.54

PROVEAN

Benign

-0.74

REVEL

Benign

0.14

Sift

Benign

0.63

Sift4G

Benign

0.43

Polyphen

0.17

Vest4

0.041

MutPred

0.14

Gain of phosphorylation at P228 (P = 0.0104)

MVP

0.80

MPC

0.32

ClinPred

0.077

GERP RS

3.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.037

gMVP

0.19

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over