Variant 12-6967172-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4BS2

The NM_001144831.2(PHB2):c.788C>T(p.Thr263Met) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000701 in 1,569,376 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000056 ( 0 hom. )

Consequence

PHB2
NM_001144831.2 missense, splice_region

Scores

Splicing: ADA: 0.06367

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 9.85

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -5 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.37221608).

BS2

High AC in GnomAdExome4 at 8 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PHB2	NM_001144831.2 linkuse as main transcript	c.788C>T	p.Thr263Met	missense_variant, splice_region_variant	7/10	ENST00000535923.6	NP_001138303.1	Q99623-1
PHB2	NM_001267700.1 linkuse as main transcript	c.674C>T	p.Thr225Met	missense_variant, splice_region_variant	6/9		NP_001254629.1	Q99623-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PHB2	ENST00000535923.6 linkuse as main transcript	c.788C>T	p.Thr263Met	missense_variant, splice_region_variant	7/10	5	NM_001144831.2	ENSP00000441875.1		Q99623-1

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152220

Hom.:

Cov.:

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:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000110

AC:

AN:

181340

Hom.:

AF XY:

0.00

AC XY:

AN XY:

97216

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000746

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000565

AC:

AN:

1417156

Hom.:

Cov.:

AF XY:

0.00000285

AC XY:

AN XY:

701068

show subpopulations

Gnomad4 AFR exome

AF:

0.0000309

Gnomad4 AMR exome

AF:

0.0000533

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:

0.00000459

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152220

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74362

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:

0.0000294

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000712

Hom.:

Bravo

AF:

0.0000264

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000121

AC:

ExAC

AF:

0.00000837

AC:

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 26, 2024

The c.788C>T (p.T263M) alteration is located in exon 7 (coding exon 7) of the PHB2 gene. This alteration results from a C to T substitution at nucleotide position 788, causing the threonine (T) at amino acid position 263 to be replaced by a methionine (M). 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

0.19

BayesDel_addAF

Pathogenic

0.21

BayesDel_noAF

Uncertain

0.060

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.59

D;T;T;.

Eigen

Uncertain

0.23

Eigen_PC

Uncertain

0.32

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.86

D;D;T;D

M_CAP

Benign

0.028

MetaRNN

Benign

0.37

T;T;T;T

MetaSVM

Benign

-0.77

MutationAssessor

Benign

1.9

L;.;.;.

PrimateAI

Pathogenic

0.81

PROVEAN

Uncertain

-3.5

D;D;D;D

REVEL

Uncertain

0.62

Sift

Benign

0.041

D;D;D;D

Sift4G

Benign

0.075

T;T;D;D

Polyphen

0.65

P;.;.;.

Vest4

0.55

MVP

0.53

MPC

0.89

ClinPred

0.90

GERP RS

5.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.36

gMVP

0.70

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.064

dbscSNV1_RF

Benign

0.29

SpliceAI score (max)

0.010

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