Genetic Variant PPARGC1B:p.Arg292Ser (chr5-149832947-C-A) – ACMG Classification: Benign (-14 pts)

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_StrongBP6_ModerateBA1

The NM_133263.4(PPARGC1B):c.874C>A(p.Arg292Ser) variant causes a missense change. The variant allele was found at a frequency of 0.0426 in 1,613,134 control chromosomes in the GnomAD database, including 2,546 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R292H) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.076 ( 748 hom., cov: 32)

Exomes 𝑓: 0.039 ( 1798 hom. )

Consequence

PPARGC1B
NM_133263.4 missense

Scores

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: 4.86

Publications

27 publications found

Variant links:

Genes affected

PPARGC1B (HGNC:30022): (PPARG coactivator 1 beta) The protein encoded by this gene stimulates the activity of several transcription factors and nuclear receptors, including estrogen receptor alpha, nuclear respiratory factor 1, and glucocorticoid receptor. The encoded protein may be involved in fat oxidation, non-oxidative glucose metabolism, and the regulation of energy expenditure. This protein is downregulated in prediabetic and type 2 diabetes mellitus patients. Certain allelic variations in this gene increase the risk of the development of obesity. Three transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Mar 2010]

PPARGC1B links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -14 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0016933084).

BP6

Variant 5-149832947-C-A is Benign according to our data. Variant chr5-149832947-C-A is described in ClinVar as Benign. ClinVar VariationId is 1288654.Status of the report is criteria_provided_single_submitter, 1 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.17 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PPARGC1B	NM_133263.4 link	c.874C>A	p.Arg292Ser	missense_variant	Exon 5 of 12	ENST00000309241.10	NP_573570.3	Q86YN6-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PPARGC1B	ENST00000309241.10 link	c.874C>A	p.Arg292Ser	missense_variant	Exon 5 of 12	1	NM_133263.4	ENSP00000312649.5		Q86YN6-1

Frequencies

GnomAD3 genomes

AF:

0.0758

AC:

11529

AN:

152090

Hom.:

746

Cov.:

show subpopulations

Gnomad AFR

AF:

0.173

Gnomad AMI

AF:

0.00768

Gnomad AMR

AF:

0.0481

Gnomad ASJ

AF:

0.0222

Gnomad EAS

AF:

0.127

Gnomad SAS

AF:

0.0726

Gnomad FIN

AF:

0.0132

Gnomad MID

AF:

0.0570

Gnomad NFE

AF:

0.0328

Gnomad OTH

AF:

0.0690

GnomAD2 exomes

AF:

0.0507

AC:

12600

AN:

248750

AF XY:

0.0494

show subpopulations

Gnomad AFR exome

AF:

0.174

Gnomad AMR exome

AF:

0.0243

Gnomad ASJ exome

AF:

0.0199

Gnomad EAS exome

AF:

0.133

Gnomad FIN exome

AF:

0.0157

Gnomad NFE exome

AF:

0.0335

Gnomad OTH exome

AF:

0.0409

GnomAD4 exome

AF:

0.0391

AC:

57194

AN:

1460926

Hom.:

1798

Cov.:

AF XY:

0.0396

AC XY:

28799

AN XY:

726744

show subpopulations

African (AFR)

AF:

0.173

AC:

5793

AN:

33480

American (AMR)

AF:

0.0261

AC:

1167

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.0196

AC:

513

AN:

26130

East Asian (EAS)

AF:

0.118

AC:

4679

AN:

39700

South Asian (SAS)

AF:

0.0689

AC:

5944

AN:

86258

European-Finnish (FIN)

AF:

0.0162

AC:

851

AN:

52484

Middle Eastern (MID)

AF:

0.0487

AC:

281

AN:

5768

European-Non Finnish (NFE)

AF:

0.0313

AC:

34794

AN:

1111998

Other (OTH)

AF:

0.0525

AC:

3172

AN:

60386

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.473

Heterozygous variant carriers

3442

6884

10327

13769

17211

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1470

2940

4410

5880

7350

<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:

0.0758

AC:

11535

AN:

152208

Hom.:

748

Cov.:

AF XY:

0.0746

AC XY:

5554

AN XY:

74430

show subpopulations

African (AFR)

AF:

0.173

AC:

7181

AN:

41508

American (AMR)

AF:

0.0480

AC:

734

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.0222

AC:

AN:

3470

East Asian (EAS)

AF:

0.127

AC:

657

AN:

5156

South Asian (SAS)

AF:

0.0722

AC:

348

AN:

4820

European-Finnish (FIN)

AF:

0.0132

AC:

140

AN:

10620

Middle Eastern (MID)

AF:

0.0510

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0328

AC:

2233

AN:

68020

Other (OTH)

AF:

0.0678

AC:

143

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

495

989

1484

1978

2473

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

132

264

396

528

660

<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:

0.0464

Hom.:

1105

Bravo

AF:

0.0830

TwinsUK

AF:

0.0326

AC:

121

ALSPAC

AF:

0.0254

AC:

ESP6500AA

AF:

0.176

AC:

776

ESP6500EA

AF:

0.0340

AC:

292

ExAC

AF:

0.0543

AC:

6588

Asia WGS

AF:

0.0970

AC:

337

AN:

3478

EpiCase

AF:

0.0322

EpiControl

AF:

0.0342

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Benign:1

Jun 09, 2021

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.44

BayesDel_addAF

Benign

-0.53

BayesDel_noAF

Benign

-0.40

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.26

.;.;T;.

Eigen

Pathogenic

0.71

Eigen_PC

Pathogenic

0.71

FATHMM_MKL

Uncertain

0.88

LIST_S2

Benign

0.64

T;T;T;T

MetaRNN

Benign

0.0017

T;T;T;T

MetaSVM

Benign

-1.3

MutationAssessor

Uncertain

2.5

.;M;M;.

PhyloP100

4.9

PrimateAI

Benign

0.44

PROVEAN

Benign

-1.8

N;N;N;N

REVEL

Benign

0.16

Sift

Pathogenic

0.0

D;D;D;D

Sift4G

Benign

0.14

T;T;D;T

Polyphen

1.0

D;D;D;.

Vest4

0.54

MPC

0.69

ClinPred

0.021

GERP RS

5.8

PromoterAI

-0.022

Neutral

(source)

Varity_R

0.37

gMVP

0.31

Mutation Taster

=92/8

polymorphism (auto)

(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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over