Genetic Variant HEBP2:p.Pro23Leu (chr6-138404563-C-T) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_014320.3(HEBP2):c.68C>T(p.Pro23Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,096 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

HEBP2
NM_014320.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.916

Variant links:

Genes affected

HEBP2 (HGNC:15716): (heme binding protein 2) The protein encoded by this gene is found predominately in the cytoplasm, where it plays a role in the collapse of mitochondrial membrane potential (MMP) prior to necrotic cell death. The encoded protein enhances outer and inner mitochondrial membrane permeabilization, especially under conditions of oxidative stress. [provided by RefSeq, May 2016]

HEBP2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HEBP2	NM_014320.3 link	c.68C>T	p.Pro23Leu	missense_variant	Exon 1 of 4	ENST00000607197.6	NP_055135.1	Q9Y5Z4-1
HEBP2	NM_001326381.2 link	c.68C>T	p.Pro23Leu	missense_variant	Exon 1 of 4		NP_001313310.1	Q5THN1
HEBP2	NM_001326380.2 link	c.136-582C>T		intron_variant	Intron 1 of 3		NP_001313309.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
HEBP2	ENST00000607197.6 link	c.68C>T	p.Pro23Leu	missense_variant	Exon 1 of 4	1	NM_014320.3	ENSP00000475750.1	Q9Y5Z4-1
HEBP2	ENST00000367697.7 link	c.68C>T	p.Pro23Leu	missense_variant	Exon 1 of 4	2		ENSP00000356670.3	Q5THN1
HEBP2	ENST00000448741.5 link	c.136-582C>T		intron_variant	Intron 1 of 3	5		ENSP00000392101.1	C9IZA0

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152096

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1158082

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

559334

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:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152096

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74282

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jan 21, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.68C>T (p.P23L) alteration is located in exon 1 (coding exon 1) of the HEBP2 gene. This alteration results from a C to T substitution at nucleotide position 68, causing the proline (P) at amino acid position 23 to be replaced by a leucine (L). 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

Uncertain

0.49

BayesDel_addAF

Benign

-0.054

BayesDel_noAF

Benign

-0.32

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.090

T;T

Eigen

Uncertain

0.24

Eigen_PC

Benign

0.11

FATHMM_MKL

Benign

0.35

LIST_S2

Benign

0.76

T;T

M_CAP

Pathogenic

0.36

MetaRNN

Uncertain

0.50

D;D

MetaSVM

Benign

-1.1

MutationAssessor

Pathogenic

2.9

M;.

PrimateAI

Pathogenic

0.81

PROVEAN

Pathogenic

-4.7

.;D

REVEL

Benign

0.23

Sift

Pathogenic

0.0

.;D

Sift4G

Uncertain

0.0080

D;D

Polyphen

1.0

D;.

Vest4

0.31

MutPred

0.70

Gain of catalytic residue at P23 (P = 0.0034);Gain of catalytic residue at P23 (P = 0.0034);

MVP

0.34

MPC

0.31

ClinPred

1.0

GERP RS

3.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.75

gMVP

0.77

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over