6-138404593-C-G

Variant names:

• chr6-138404593-C-G
• rs1774604055
• NM_014320.3:c.98C>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_014320.3(HEBP2):​c.98C>G​(p.Pro33Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000882 in 1,134,288 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. P33L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 8.8e-7 (0 hom.)
• Consequence: HEBP2 NM_014320.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.639
• Publications: 0 publications found

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

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=0.09878564).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014320.3. 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
	HEBP2	NM_014320.3	MANE Select	c.98C>G	p.Pro33Arg	missense	Exon 1 of 4	NP_055135.1	Q9Y5Z4-1
	HEBP2	NM_001326381.2		c.98C>G	p.Pro33Arg	missense	Exon 1 of 4	NP_001313310.1	Q5THN1
	HEBP2	NM_001326380.2		c.136-552C>G		intron	N/A	NP_001313309.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HEBP2	ENST00000607197.6	TSL:1 MANE Select	c.98C>G	p.Pro33Arg	missense	Exon 1 of 4	ENSP00000475750.1	Q9Y5Z4-1
	HEBP2	ENST00000858693.1		c.98C>G	p.Pro33Arg	missense	Exon 1 of 5	ENSP00000528752.1
	HEBP2	ENST00000367697.7	TSL:2	c.98C>G	p.Pro33Arg	missense	Exon 1 of 4	ENSP00000356670.3	Q5THN1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 8.82e-7 AC: 1 AN: 1134288 Hom.: 0 Cov.: 30 AF XY: 0.00000184 AC XY: 1 AN XY: 544624

African (AFR) AF: 0.00 AC: 0 AN: 23164

American (AMR) AF: 0.00 AC: 0 AN: 8916

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 15256

East Asian (EAS) AF: 0.00 AC: 0 AN: 26798

South Asian (SAS) AF: 0.00 AC: 0 AN: 37204

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 24870

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3068

European-Non Finnish (NFE) AF: 0.00000105 AC: 1 AN: 949336

Other (OTH) AF: 0.00 AC: 0 AN: 45676

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.096
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.64
CADD	Benign	20
DANN	Benign	0.83
DEOGEN2	Benign	0.0092	T
Eigen	Benign	-0.71
Eigen_PC	Benign	-0.68
FATHMM_MKL	Benign	0.14	N
LIST_S2	Benign	0.51	T
M_CAP	Benign	0.037	D
MetaRNN	Benign	0.099	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	1.3	L
PhyloP100		0.64
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	-0.40	N
REVEL	Benign	0.052
Sift	Benign	0.12	T
Sift4G	Benign	0.20	T
Polyphen		0.0020	B
Vest4		0.062
MutPred		0.43		Gain of solvent accessibility (P = 0.0216)
MVP		0.33
MPC		0.047
ClinPred		0.042	T
GERP RS		2.1
PromoterAI		-0.041	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.14
gMVP		0.27
Mutation Taster		=92/8	polymorphism

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

Other links and lift over

dbSNP: rs1774604055; hg19: chr6-138725730;