17-48543540-C-G

Variant names:

• chr17-48543540-C-G
• rs150329872
• NM_002145.4:c.599G>C

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 1P and 6B. PP3 BP4_Moderate BS2

The NM_002145.4(HOXB2):​c.599G>C​(p.Arg200Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000183 in 1,612,922 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00018 (1 hom., cov: 31)
  • Exomes 𝑓: 0.00018 (1 hom.)
• Consequence: HOXB2 NM_002145.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.71

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]

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

ACMG classification

Verdict is Likely_benign. Variant got -5 ACMG points.

• PP3: Multiple lines of computational evidence support a deleterious effect 11: AlphaMissense, BayesDel_addAF, BayesDel_noAF, Cadd, Eigen, M_CAP, MutationAssessor, phyloP100way_vertebrate, PrimateAI, PROVEAN, REVEL [when max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]
• BP4: Computational evidence support a benign effect (MetaRNN=0.20533663).
• BS2: High AC in GnomAd4 at 28 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HOXB2	NM_002145.4	c.599G>C	p.Arg200Pro	missense_variant	Exon 2 of 2	ENST00000330070.6	NP_002136.1
HOXB2	XM_005257275.5	c.272G>C	p.Arg91Pro	missense_variant	Exon 2 of 2		XP_005257332.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HOXB2	ENST00000330070.6	c.599G>C	p.Arg200Pro	missense_variant	Exon 2 of 2	1	NM_002145.4	ENSP00000331741.4
HOXB2	ENST00000571287.1	n.244G>C		non_coding_transcript_exon_variant	Exon 2 of 2	3
HOXB-AS1	ENST00000504972.3	n.-11C>G		upstream_gene_variant		3

Frequencies

GnomAD3 genomes AF: 0.000184 AC: 28 AN: 152114 Hom.: 1 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00663

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000397 AC: 98 AN: 246658 Hom.: 0 AF XY: 0.000416 AC XY: 56 AN XY: 134514

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000290

Gnomad ASJ exome AF: 0.00793

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000328

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000127

Gnomad OTH exome AF: 0.000494

GnomAD4 exome AF: 0.000183 AC: 267 AN: 1460808 Hom.: 1 Cov.: 33 AF XY: 0.000194 AC XY: 141 AN XY: 726736

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00750

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000324

Gnomad4 OTH exome AF: 0.000513

GnomAD4 genome AF: 0.000184 AC: 28 AN: 152114 Hom.: 1 Cov.: 31 AF XY: 0.000202 AC XY: 15 AN XY: 74308

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.0000655

Gnomad4 ASJ AF: 0.00663

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.000478

Alfa AF: 0.000592 Hom.: 1

Bravo AF: 0.000234

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000355 AC: 3

ExAC AF: 0.000347 AC: 42

EpiCase AF: 0.0000545

EpiControl AF: 0.000296

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jul 06, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.599G>C (p.R200P) alteration is located in exon 2 (coding exon 2) of the HOXB2 gene. This alteration results from a G to C substitution at nucleotide position 599, causing the arginine (R) at amino acid position 200 to be replaced by a proline (P). 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	0.40	D
BayesDel_noAF	Pathogenic	0.56
CADD	Pathogenic	34
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.95	D
Eigen	Pathogenic	0.92
Eigen_PC	Pathogenic	0.82
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.97	D
M_CAP	Pathogenic	0.83	D
MetaRNN	Benign	0.21	T
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.8	H
PrimateAI	Pathogenic	0.88	D
PROVEAN	Pathogenic	-6.2	D
REVEL	Pathogenic	0.97
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.95
MVP		0.97
MPC		1.3
ClinPred		0.36	T
GERP RS		4.6
Varity_R		0.95
gMVP		0.68

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

LitVar

Other links and lift over

dbSNP: rs150329872; hg19: chr17-46620902;