6-138404563-C-T

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

5
5
9

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]

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
HEBP2NM_014320.3 linkc.68C>T p.Pro23Leu missense_variant Exon 1 of 4 ENST00000607197.6 NP_055135.1 Q9Y5Z4-1
HEBP2NM_001326381.2 linkc.68C>T p.Pro23Leu missense_variant Exon 1 of 4 NP_001313310.1 Q5THN1
HEBP2NM_001326380.2 linkc.136-582C>T intron_variant Intron 1 of 3 NP_001313309.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
HEBP2ENST00000607197.6 linkc.68C>T p.Pro23Leu missense_variant Exon 1 of 4 1 NM_014320.3 ENSP00000475750.1 Q9Y5Z4-1
HEBP2ENST00000367697.7 linkc.68C>T p.Pro23Leu missense_variant Exon 1 of 4 2 ENSP00000356670.3 Q5THN1
HEBP2ENST00000448741.5 linkc.136-582C>T intron_variant Intron 1 of 3 5 ENSP00000392101.1 C9IZA0

Frequencies

GnomAD3 genomes
AF:
0.00000657
AC:
1
AN:
152096
Hom.:
0
Cov.:
33
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:
0
AN:
1158082
Hom.:
0
Cov.:
30
AF XY:
0.00
AC XY:
0
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:
1
AN:
152096
Hom.:
0
Cov.:
33
AF XY:
0.00
AC XY:
0
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
T
BayesDel_noAF
Benign
-0.32
CADD
Uncertain
25
DANN
Uncertain
1.0
DEOGEN2
Benign
0.090
T;T
Eigen
Uncertain
0.24
Eigen_PC
Benign
0.11
FATHMM_MKL
Benign
0.35
N
LIST_S2
Benign
0.76
T;T
M_CAP
Pathogenic
0.36
D
MetaRNN
Uncertain
0.50
D;D
MetaSVM
Benign
-1.1
T
MutationAssessor
Pathogenic
2.9
M;.
PrimateAI
Pathogenic
0.81
D
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
D
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.

Other links and lift over

dbSNP: rs1774602352; hg19: chr6-138725700; API