NM_014320.3:c.20C>T

Variant names:

• chr6-138404515-C-T
• rs1390441413
• NM_014320.3:c.20C>T

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.20C>T​(p.Pro7Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000228 in 1,315,554 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 33)
  • Exomes 𝑓: 8.6e-7 (0 hom.)
• Consequence: HEBP2 NM_014320.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.02
• 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=0.092024654).

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.20C>T	p.Pro7Leu	missense	Exon 1 of 4	NP_055135.1	Q9Y5Z4-1
	HEBP2	NM_001326381.2		c.20C>T	p.Pro7Leu	missense	Exon 1 of 4	NP_001313310.1	Q5THN1
	HEBP2	NM_001326380.2		c.136-630C>T		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.20C>T	p.Pro7Leu	missense	Exon 1 of 4	ENSP00000475750.1	Q9Y5Z4-1
	HEBP2	ENST00000858693.1		c.20C>T	p.Pro7Leu	missense	Exon 1 of 5	ENSP00000528752.1
	HEBP2	ENST00000367697.7	TSL:2	c.20C>T	p.Pro7Leu	missense	Exon 1 of 4	ENSP00000356670.3	Q5THN1

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152062 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000194

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 AF: 8.60e-7 AC: 1 AN: 1163384 Hom.: 0 Cov.: 30 AF XY: 0.00000178 AC XY: 1 AN XY: 563222

African (AFR) AF: 0.0000421 AC: 1 AN: 23726

American (AMR) AF: 0.00 AC: 0 AN: 12274

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 16916

East Asian (EAS) AF: 0.00 AC: 0 AN: 26978

South Asian (SAS) AF: 0.00 AC: 0 AN: 43442

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 26026

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3198

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 964012

Other (OTH) AF: 0.00 AC: 0 AN: 46812

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152170 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 74402

African (AFR) AF: 0.0000241 AC: 1 AN: 41548

American (AMR) AF: 0.00 AC: 0 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.000195 AC: 1 AN: 5140

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10594

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67980

Other (OTH) AF: 0.00 AC: 0 AN: 2116

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000264

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.037	T
BayesDel_noAF	Benign	-0.29
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.017	T
Eigen	Benign	-0.79
Eigen_PC	Benign	-0.82
FATHMM_MKL	Benign	0.090	N
LIST_S2	Benign	0.64	T
M_CAP	Benign	0.055	D
MetaRNN	Benign	0.092	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.8	L
PhyloP100		1.0
PrimateAI	Uncertain	0.77	T
PROVEAN	Benign	0.11	N
REVEL	Benign	0.063
Sift	Uncertain	0.0070	D
Sift4G	Uncertain	0.022	D
Polyphen		0.0050	B
Vest4		0.30
MutPred		0.28		Loss of relative solvent accessibility (P = 0.0186)
MVP		0.44
MPC		0.086
ClinPred		0.25	T
GERP RS		1.9
PromoterAI		-0.029	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.065
gMVP		0.50
Mutation Taster		=95/5	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: rs1390441413; hg19: chr6-138725652;