Genetic Variant PYGO2:p.Lys261Glu (chr1-154959219-T-C) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_138300.4(PYGO2):c.781A>G(p.Lys261Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000391 in 1,566,462 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/22 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 0.00030 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00040 ( 1 hom. )

Consequence

PYGO2
NM_138300.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.48

Publications

4 publications found

Variant links:

Genes affected

PYGO2 (HGNC:30257): (pygopus family PHD finger 2) Predicted to enable several functions, including chromatin binding activity; histone acetyltransferase regulator activity; and histone binding activity. Predicted to be involved in kidney development and spermatid nucleus differentiation. Predicted to act upstream of or within several processes, including animal organ development; positive regulation of chromatin binding activity; and regulation of histone H3-K4 methylation. Part of beta-catenin-TCF complex. [provided by Alliance of Genome Resources, Apr 2022]

PYGO2 links:

ENSG00000310191 (HGNC:):

ENSG00000310191 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.032338828).

BS2

High AC in GnomAd4 at 45 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PYGO2	NM_138300.4 link	c.781A>G	p.Lys261Glu	missense_variant	Exon 3 of 3	ENST00000368457.3	NP_612157.1	Q9BRQ0Q5T170

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
PYGO2	ENST00000368457.3 link	c.781A>G	p.Lys261Glu	missense_variant	Exon 3 of 3	1	NM_138300.4	ENSP00000357442.2	Q9BRQ0
PYGO2	ENST00000368456.1 link	c.670A>G	p.Lys224Glu	missense_variant	Exon 3 of 3	2		ENSP00000357441.1	Q5T171
ENSG00000310191	ENST00000848032.1 link	n.424-1662T>C		intron_variant	Intron 2 of 2
ENSG00000310191	ENST00000848033.1 link	n.401-1662T>C		intron_variant	Intron 2 of 2

Frequencies

GnomAD3 genomes

AF:

0.000296

AC:

AN:

151814

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000218

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000197

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:

0.000486

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000225

AC:

AN:

195718

AF XY:

0.000246

show subpopulations

Gnomad AFR exome

AF:

0.000145

Gnomad AMR exome

AF:

0.000227

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000385

Gnomad OTH exome

AF:

0.000429

GnomAD4 exome

AF:

0.000402

AC:

568

AN:

1414530

Hom.:

Cov.:

AF XY:

0.000366

AC XY:

256

AN XY:

699464

show subpopulations

African (AFR)

AF:

0.0000312

AC:

AN:

32048

American (AMR)

AF:

0.000189

AC:

AN:

37030

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

23004

East Asian (EAS)

AF:

0.00

AC:

AN:

39056

South Asian (SAS)

AF:

0.00

AC:

AN:

79368

European-Finnish (FIN)

AF:

0.00

AC:

AN:

50874

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5536

European-Non Finnish (NFE)

AF:

0.000500

AC:

545

AN:

1089392

Other (OTH)

AF:

0.000258

AC:

AN:

58222

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.474

Heterozygous variant carriers

125

156

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

120

<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:

0.000296

AC:

AN:

151932

Hom.:

Cov.:

AF XY:

0.000229

AC XY:

AN XY:

74284

show subpopulations

African (AFR)

AF:

0.000217

AC:

AN:

41416

American (AMR)

AF:

0.000197

AC:

AN:

15262

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5144

South Asian (SAS)

AF:

0.00

AC:

AN:

4808

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10572

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000486

AC:

AN:

67946

Other (OTH)

AF:

0.00

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

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:

0.000331

Hom.:

Bravo

AF:

0.000306

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000519

AC:

ExAC

AF:

0.000182

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.56

BayesDel_addAF

Benign

-0.33

BayesDel_noAF

Benign

-0.39

CADD

Benign

(source)

DANN

Benign

0.83

DEOGEN2

Benign

0.17

T;.

Eigen

Benign

-0.31

Eigen_PC

Benign

-0.14

FATHMM_MKL

Uncertain

0.89

LIST_S2

Benign

0.75

T;T

M_CAP

Benign

0.0075

MetaRNN

Benign

0.032

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.69

N;.

PhyloP100

1.5

PrimateAI

Uncertain

0.67

PROVEAN

Benign

0.060

N;N

REVEL

Benign

0.22

Sift

Benign

0.82

T;T

Sift4G

Benign

1.0

T;T

Polyphen

0.43

B;.

Vest4

0.17

MVP

0.66

MPC

0.71

ClinPred

0.030

GERP RS

4.7

Varity_R

0.13

gMVP

0.48

Mutation Taster

=91/9

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over