Genetic Variant PPARGC1B:p.Tyr21Cys (chr5-149730404-A-G) – ACMG Classification: Likely_benign (-5 pts)

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4BS2

The NM_133263.4(PPARGC1B):c.62A>G(p.Tyr21Cys) variant causes a missense change. The variant allele was found at a frequency of 0.0000198 in 1,565,160 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000046 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000017 ( 0 hom. )

Consequence

PPARGC1B
NM_133263.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.11

Publications

0 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: Likely_benign. The variant received -5 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.38585788).

BS2

High AC in GnomAd4 at 7 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_133263.4. 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
	PPARGC1B	NM_133263.4	MANE Select	c.62A>G	p.Tyr21Cys	missense	Exon 1 of 12	NP_573570.3
	PPARGC1B	NM_001172698.2		c.62A>G	p.Tyr21Cys	missense	Exon 1 of 11	NP_001166169.1	Q86YN6-5

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PPARGC1B	ENST00000309241.10	TSL:1 MANE Select	c.62A>G	p.Tyr21Cys	missense	Exon 1 of 12	ENSP00000312649.5	Q86YN6-1
PPARGC1B	ENST00000394320.7	TSL:1	c.62A>G	p.Tyr21Cys	missense	Exon 1 of 11	ENSP00000377855.3	Q86YN6-3
PPARGC1B	ENST00000360453.8	TSL:1	c.62A>G	p.Tyr21Cys	missense	Exon 1 of 11	ENSP00000353638.4	Q86YN6-5

Frequencies

GnomAD3 genomes

AF:

0.0000462

AC:

AN:

151594

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000169

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000269

AC:

AN:

185810

AF XY:

0.0000198

show subpopulations

Gnomad AFR exome

AF:

0.000347

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000242

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000170

AC:

AN:

1413566

Hom.:

Cov.:

AF XY:

0.0000143

AC XY:

AN XY:

700748

show subpopulations

African (AFR)

AF:

0.000167

AC:

AN:

29910

American (AMR)

AF:

0.00

AC:

AN:

39160

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24884

East Asian (EAS)

AF:

0.0000848

AC:

AN:

35394

South Asian (SAS)

AF:

0.000113

AC:

AN:

79346

European-Finnish (FIN)

AF:

0.00

AC:

AN:

50772

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5438

European-Non Finnish (NFE)

AF:

0.00000459

AC:

AN:

1090262

Other (OTH)

AF:

0.0000342

AC:

AN:

58400

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

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

GnomAD4 genome

AF:

0.0000462

AC:

AN:

151594

Hom.:

Cov.:

AF XY:

0.0000540

AC XY:

AN XY:

74038

show subpopulations

African (AFR)

AF:

0.000169

AC:

AN:

41314

American (AMR)

AF:

0.00

AC:

AN:

15260

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5118

South Asian (SAS)

AF:

0.00

AC:

AN:

4812

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10514

Middle Eastern (MID)

AF:

0.00

AC:

AN:

310

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67810

Other (OTH)

AF:

0.00

AC:

AN:

2076

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.511

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

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:

0.0000387

Hom.:

Bravo

AF:

0.0000529

ESP6500AA

AF:

0.000688

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000418

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3468

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.62

BayesDel_addAF

Benign

-0.17

BayesDel_noAF

Benign

-0.24

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.13

Eigen

Uncertain

0.31

Eigen_PC

Uncertain

0.30

FATHMM_MKL

Uncertain

0.87

LIST_S2

Benign

0.80

M_CAP

Pathogenic

0.68

MetaRNN

Benign

0.39

MetaSVM

Benign

-1.2

MutationAssessor

Benign

1.2

PhyloP100

4.1

PrimateAI

Pathogenic

0.89

PROVEAN

Benign

-0.66

REVEL

Benign

0.25

Sift

Pathogenic

0.0

Sift4G

Uncertain

0.0080

Polyphen

1.0

Vest4

0.53

MVP

0.23

MPC

0.61

ClinPred

0.47

GERP RS

3.6

PromoterAI

-0.056

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.29

gMVP

0.39

Mutation Taster

=56/44

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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