6-138404589-G-C

Position:

• chr6-138404589-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_014320.3(HEBP2):​c.94G>C​(p.Gly32Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000011 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: HEBP2 NM_014320.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.411

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.0963026).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HEBP2	NM_014320.3	c.94G>C	p.Gly32Arg	missense_variant	1/4	ENST00000607197.6	NP_055135.1
HEBP2	NM_001326381.2	c.94G>C	p.Gly32Arg	missense_variant	1/4		NP_001313310.1
HEBP2	NM_001326380.2	c.136-556G>C		intron_variant			NP_001313309.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HEBP2	ENST00000607197.6	c.94G>C	p.Gly32Arg	missense_variant	1/4	1	NM_014320.3	ENSP00000475750.1
HEBP2	ENST00000367697.7	c.94G>C	p.Gly32Arg	missense_variant	1/4	2		ENSP00000356670.3
HEBP2	ENST00000448741.5	c.136-556G>C		intron_variant		5		ENSP00000392101.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000106 AC: 12 AN: 1136332 Hom.: 0 Cov.: 30 AF XY: 0.00000549 AC XY: 3 AN XY: 546014

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: 0.0000116

Gnomad4 OTH exome AF: 0.0000218

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 09, 2022

The c.94G>C (p.G32R) alteration is located in exon 1 (coding exon 1) of the HEBP2 gene. This alteration results from a G to C substitution at nucleotide position 94, causing the glycine (G) at amino acid position 32 to be replaced by an arginine (R). 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	Benign	0.17
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	17
DANN	Uncertain	0.98
DEOGEN2	Benign	0.0078	T;T
Eigen	Benign	-0.81
Eigen_PC	Benign	-0.93
FATHMM_MKL	Benign	0.12	N
LIST_S2	Benign	0.71	T;T
M_CAP	Benign	0.039	D
MetaRNN	Benign	0.096	T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	1.3	L;.
PrimateAI	Uncertain	0.68	T
PROVEAN	Benign	-0.10	.;N
REVEL	Benign	0.027
Sift	Benign	0.23	.;T
Sift4G	Benign	0.12	T;T
Polyphen		0.70	P;.
Vest4		0.19
MutPred		0.49		Gain of solvent accessibility (P = 0.0097);Gain of solvent accessibility (P = 0.0097);
MVP		0.30
MPC		0.11
ClinPred		0.23	T
GERP RS		1.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.17
gMVP		0.50

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: rs1774603849; hg19: chr6-138725726;