Genetic Variant PTTG2:p.Arg44Pro (chr4-37960565-G-C) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_006607.3(PTTG2):c.131G>C(p.Arg44Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.594 in 1,613,780 control chromosomes in the GnomAD database, including 290,836 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.63 ( 31437 hom., cov: 31)

Exomes 𝑓: 0.59 ( 259399 hom. )

Consequence

PTTG2
NM_006607.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.237

Publications

28 publications found

Variant links:

Genes affected

PTTG2 (HGNC:9691): (pituitary tumor-transforming 2) Predicted to enable SH3 domain binding activity. Predicted to be involved in homologous chromosome segregation and negative regulation of mitotic sister chromatid separation. Predicted to be located in cytoplasm. Predicted to be active in nucleus. [provided by Alliance of Genome Resources, Apr 2022]

PTTG2 links:

TBC1D1 (HGNC:11578): (TBC1 domain family member 1) TBC1D1 is the founding member of a family of proteins sharing a 180- to 200-amino acid TBC domain presumed to have a role in regulating cell growth and differentiation. These proteins share significant homology with TRE2 (USP6; MIM 604334), yeast Bub2, and CDC16 (MIM 603461) (White et al., 2000 [PubMed 10965142]).[supplied by OMIM, Mar 2008]

TBC1D1 Gene-Disease associations (from GenCC):

congenital anomaly of kidney and urinary tract
Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

TBC1D1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=8.6032E-7).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.935 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PTTG2	NM_006607.3 link	c.131G>C	p.Arg44Pro	missense_variant	Exon 1 of 1	ENST00000504686.2	NP_006598.2	Q9NZH5-2
TBC1D1	NM_001396959.1 link	c.418-53944G>C		intron_variant	Intron 2 of 21	ENST00000698857.1	NP_001383888.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PTTG2	ENST00000504686.2 link	c.131G>C	p.Arg44Pro	missense_variant	Exon 1 of 1	6	NM_006607.3	ENSP00000424261.1		Q9NZH5-2
TBC1D1	ENST00000698857.1 link	c.418-53944G>C		intron_variant	Intron 2 of 21		NM_001396959.1	ENSP00000513987.1		A0A8V8TNS9

Frequencies

GnomAD3 genomes

AF:

0.635

AC:

96394

AN:

151906

Hom.:

31374

Cov.:

show subpopulations

Gnomad AFR

AF:

0.704

Gnomad AMI

AF:

0.378

Gnomad AMR

AF:

0.699

Gnomad ASJ

AF:

0.618

Gnomad EAS

AF:

0.957

Gnomad SAS

AF:

0.676

Gnomad FIN

AF:

0.592

Gnomad MID

AF:

0.579

Gnomad NFE

AF:

0.562

Gnomad OTH

AF:

0.628

GnomAD2 exomes

AF:

0.646

AC:

162039

AN:

250724

AF XY:

0.637

show subpopulations

Gnomad AFR exome

AF:

0.715

Gnomad AMR exome

AF:

0.764

Gnomad ASJ exome

AF:

0.627

Gnomad EAS exome

AF:

0.957

Gnomad FIN exome

AF:

0.598

Gnomad NFE exome

AF:

0.556

Gnomad OTH exome

AF:

0.616

GnomAD4 exome

AF:

0.590

AC:

861839

AN:

1461756

Hom.:

259399

Cov.:

AF XY:

0.591

AC XY:

429599

AN XY:

727194

show subpopulations

African (AFR)

AF:

0.701

AC:

23474

AN:

33476

American (AMR)

AF:

0.752

AC:

33641

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.627

AC:

16399

AN:

26134

East Asian (EAS)

AF:

0.961

AC:

38135

AN:

39700

South Asian (SAS)

AF:

0.666

AC:

57440

AN:

86256

European-Finnish (FIN)

AF:

0.593

AC:

31686

AN:

53412

Middle Eastern (MID)

AF:

0.576

AC:

3325

AN:

5768

European-Non Finnish (NFE)

AF:

0.558

AC:

620553

AN:

1111898

Other (OTH)

AF:

0.616

AC:

37186

AN:

60388

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.480

Heterozygous variant carriers

20243

40486

60729

80972

101215

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

17574

35148

52722

70296

87870

<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:

0.635

AC:

96518

AN:

152024

Hom.:

31437

Cov.:

AF XY:

0.641

AC XY:

47624

AN XY:

74320

show subpopulations

African (AFR)

AF:

0.705

AC:

29211

AN:

41438

American (AMR)

AF:

0.699

AC:

10682

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.618

AC:

2144

AN:

3472

East Asian (EAS)

AF:

0.957

AC:

4946

AN:

5168

South Asian (SAS)

AF:

0.675

AC:

3261

AN:

4832

European-Finnish (FIN)

AF:

0.592

AC:

6246

AN:

10548

Middle Eastern (MID)

AF:

0.595

AC:

175

AN:

294

European-Non Finnish (NFE)

AF:

0.562

AC:

38173

AN:

67970

Other (OTH)

AF:

0.632

AC:

1337

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1762

3524

5285

7047

8809

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

778

1556

2334

3112

3890

<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:

0.574

Hom.:

14239

Bravo

AF:

0.648

TwinsUK

AF:

0.552

AC:

2047

ALSPAC

AF:

0.554

AC:

2135

ESP6500AA

AF:

0.704

AC:

3099

ESP6500EA

AF:

0.565

AC:

4855

ExAC

AF:

0.641

AC:

77768

Asia WGS

AF:

0.822

AC:

2855

AN:

3478

EpiCase

AF:

0.555

EpiControl

AF:

0.558

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.045

BayesDel_addAF

Benign

-0.78

BayesDel_noAF

Benign

-0.74

CADD

Benign

0.47

(source)

DANN

Benign

0.41

Eigen

Benign

-2.2

Eigen_PC

Benign

-2.2

FATHMM_MKL

Benign

0.00021

LIST_S2

Benign

0.12

MetaRNN

Benign

8.6e-7

MetaSVM

Benign

-0.93

MutationAssessor

Benign

-2.3

PhyloP100

-0.24

PrimateAI

Benign

0.34

PROVEAN

Benign

5.1

REVEL

Benign

0.058

Sift

Benign

1.0

Sift4G

Benign

1.0

Polyphen

0.0

Vest4

0.034

MPC

0.030

ClinPred

0.0012

GERP RS

-4.0

PromoterAI

-0.0038

Neutral

(source)

gMVP

0.046

Mutation Taster

=95/5

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

Computational scores

Splicing

Publications

Other links and lift over