Variant 12-6967964-G-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The NM_001144831.2(PHB2):c.535C>G(p.Leu179Val) variant causes a missense change. The variant allele was found at a frequency of 0.00000124 in 1,613,264 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

PHB2
NM_001144831.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.54

Variant links:

Genes affected

PHB2 (HGNC:30306): (prohibitin 2) Enables several functions, including protein C-terminus binding activity; protein N-terminus binding activity; and protein dimerization activity. Involved in several processes, including defense response to virus; positive regulation of cell cycle phase transition; and regulation of transcription, DNA-templated. Located in several cellular components, including cell surface; mitochondrial membrane; and nuclear matrix. Part of mitochondrial prohibitin complex. [provided by Alliance of Genome Resources, Apr 2022]

PHB2 links:

PHB2 (HGNC:):

PHB2 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.753

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PHB2	NM_001144831.2 linkuse as main transcript	c.535C>G	p.Leu179Val	missense_variant	5/10	ENST00000535923.6	NP_001138303.1	Q99623-1
PHB2	NM_001267700.1 linkuse as main transcript	c.535C>G	p.Leu179Val	missense_variant	5/9		NP_001254629.1	Q99623-2
PHB2	XM_047428234.1 linkuse as main transcript	c.535C>G	p.Leu179Val	missense_variant	5/6		XP_047284190.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PHB2	ENST00000535923.6 linkuse as main transcript	c.535C>G	p.Leu179Val	missense_variant	5/10	5	NM_001144831.2	ENSP00000441875.1		Q99623-1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152210

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

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

AF:

6.84e-7

AC:

AN:

1461054

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

726748

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000224

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:

152210

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74348

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000654

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

Bravo

AF:

0.0000113

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 17, 2023

The c.535C>G (p.L179V) alteration is located in exon 5 (coding exon 5) of the PHB2 gene. This alteration results from a C to G substitution at nucleotide position 535, causing the leucine (L) at amino acid position 179 to be replaced by a valine (V). 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

0.45

BayesDel_addAF

Pathogenic

0.35

BayesDel_noAF

Pathogenic

0.26

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.72

D;D;D;.;D;D

Eigen

Benign

0.064

Eigen_PC

Benign

0.14

FATHMM_MKL

Uncertain

0.97

LIST_S2

Uncertain

0.93

D;D;D;D;D;D

M_CAP

Uncertain

0.15

MetaRNN

Pathogenic

0.75

D;D;D;D;D;D

MetaSVM

Uncertain

0.44

MutationAssessor

Benign

1.7

L;.;.;L;.;.

PrimateAI

Pathogenic

0.85

PROVEAN

Benign

-2.2

N;N;N;N;N;N

REVEL

Pathogenic

0.68

Sift

Uncertain

0.021

D;D;D;D;D;D

Sift4G

Uncertain

0.025

D;D;D;D;.;.

Polyphen

0.025

B;.;.;.;.;.

Vest4

0.66

MutPred

0.51

Gain of catalytic residue at D181 (P = 0.0067);Gain of catalytic residue at D181 (P = 0.0067);Gain of catalytic residue at D181 (P = 0.0067);Gain of catalytic residue at D181 (P = 0.0067);.;.;

MVP

0.87

MPC

0.85

ClinPred

0.87

GERP RS

3.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.19

gMVP

0.71

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