Genetic Variant PHB2:p.Thr274Thr (chr12-6966468-T-C) – ACMG Classification: Benign (-21 pts)

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_001144831.2(PHB2):c.822A>G(p.Thr274Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00216 in 1,611,336 control chromosomes in the GnomAD database, including 92 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0056 ( 10 hom., cov: 32)

Exomes 𝑓: 0.0018 ( 82 hom. )

Consequence

PHB2
NM_001144831.2 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -0.779

Publications

3 publications found

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:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -21 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0037773252).

BP6

Variant 12-6966468-T-C is Benign according to our data. Variant chr12-6966468-T-C is described in ClinVar as Benign. ClinVar VariationId is 709112.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.779 with no splicing effect.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00562 (856/152322) while in subpopulation AFR AF = 0.0175 (728/41576). AF 95% confidence interval is 0.0165. There are 10 homozygotes in GnomAd4. There are 425 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 856 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001144831.2. 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
	PHB2	NM_001144831.2	MANE Select	c.822A>G	p.Thr274Thr	synonymous	Exon 8 of 10	NP_001138303.1	Q99623-1
	PHB2	NM_001267700.1		c.708A>G	p.Thr236Thr	synonymous	Exon 7 of 9	NP_001254629.1	Q99623-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PHB2	ENST00000535923.6	TSL:5 MANE Select	c.822A>G	p.Thr274Thr	synonymous	Exon 8 of 10	ENSP00000441875.1	Q99623-1
PHB2	ENST00000546111.5	TSL:2	c.245A>G	p.Gln82Arg	missense	Exon 3 of 4	ENSP00000438634.1	F5H2D2
PHB2	ENST00000925249.1		c.822A>G	p.Thr274Thr	synonymous	Exon 8 of 9	ENSP00000595308.1

Frequencies

GnomAD3 genomes

AF:

0.00560

AC:

853

AN:

152204

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0175

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00216

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.0121

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000265

Gnomad OTH

AF:

0.00623

GnomAD2 exomes

AF:

0.00152

AC:

379

AN:

249328

AF XY:

0.00123

show subpopulations

Gnomad AFR exome

AF:

0.0171

Gnomad AMR exome

AF:

0.00116

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00245

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000142

Gnomad OTH exome

AF:

0.00165

GnomAD4 exome

AF:

0.00180

AC:

2628

AN:

1459014

Hom.:

Cov.:

AF XY:

0.00171

AC XY:

1238

AN XY:

726044

show subpopulations

African (AFR)

AF:

0.0178

AC:

593

AN:

33400

American (AMR)

AF:

0.00150

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26116

East Asian (EAS)

AF:

0.0398

AC:

1579

AN:

39686

South Asian (SAS)

AF:

0.000174

AC:

AN:

86202

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53402

Middle Eastern (MID)

AF:

0.00226

AC:

AN:

5762

European-Non Finnish (NFE)

AF:

0.000218

AC:

242

AN:

1109458

Other (OTH)

AF:

0.00197

AC:

119

AN:

60266

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.473

Heterozygous variant carriers

117

234

351

468

585

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

120

160

200

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00562

AC:

856

AN:

152322

Hom.:

Cov.:

AF XY:

0.00571

AC XY:

425

AN XY:

74494

show subpopulations

African (AFR)

AF:

0.0175

AC:

728

AN:

41576

American (AMR)

AF:

0.00216

AC:

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.0122

AC:

AN:

5184

South Asian (SAS)

AF:

0.000207

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10628

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000265

AC:

AN:

68028

Other (OTH)

AF:

0.00617

AC:

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

131

174

218

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00418

Hom.:

Bravo

AF:

0.00587

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.0141

AC:

ESP6500EA

AF:

0.000235

AC:

ExAC

AF:

0.00182

AC:

220

Asia WGS

AF:

0.00924

AC:

AN:

3478

EpiCase

AF:

0.000109

EpiControl

AF:

0.00

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.062

BayesDel_addAF

Benign

-0.79

BayesDel_noAF

Benign

-0.85

CADD

Benign

0.51

(source)

DANN

Benign

0.51

DEOGEN2

Benign

0.0093

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.6

FATHMM_MKL

Benign

0.11

LIST_S2

Benign

0.18

MetaRNN

Benign

0.0038

MetaSVM

Benign

-0.69

PhyloP100

-0.78

PROVEAN

Benign

-0.53

REVEL

Benign

0.063

Sift

Benign

0.072

Vest4

0.090

MVP

0.11

ClinPred

0.013

GERP RS

-12

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=97/3

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over