Genetic Variant PYGO2:p.Pro235Ser (chr1-154959297-G-A) – ACMG Classification: Likely_benign (-6 pts)

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_138300.4(PYGO2):c.703C>T(p.Pro235Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00000441 in 1,586,556 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P235L) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000042 ( 0 hom. )

Consequence

PYGO2
NM_138300.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.75

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:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.093085825).

BS2

High AC in GnomAdExome4 at 6 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PYGO2	NM_138300.4 link	c.703C>T	p.Pro235Ser	missense_variant	Exon 3 of 3	ENST00000368457.3	NP_612157.1	Q9BRQ0Q5T170

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PYGO2	ENST00000368457.3 link	c.703C>T	p.Pro235Ser	missense_variant	Exon 3 of 3	1	NM_138300.4	ENSP00000357442.2		Q9BRQ0
PYGO2	ENST00000368456.1 link	c.592C>T	p.Pro198Ser	missense_variant	Exon 3 of 3	2		ENSP00000357441.1		Q5T171

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152216

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

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

GnomAD3 exomes

AF:

0.0000225

AC:

AN:

221778

Hom.:

AF XY:

0.0000167

AC XY:

AN XY:

120074

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000138

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000984

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000418

AC:

AN:

1434340

Hom.:

Cov.:

AF XY:

0.00000421

AC XY:

AN XY:

712480

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000770

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000273

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152216

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74364

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000868

Hom.:

Bravo

AF:

0.0000189

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Feb 12, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.703C>T (p.P235S) alteration is located in exon 3 (coding exon 3) of the PYGO2 gene. This alteration results from a C to T substitution at nucleotide position 703, causing the proline (P) at amino acid position 235 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.064

BayesDel_addAF

Benign

-0.35

BayesDel_noAF

Benign

-0.49

CADD

Benign

DANN

Benign

0.83

DEOGEN2

Benign

0.14

T;.

Eigen

Benign

-0.41

Eigen_PC

Benign

-0.23

FATHMM_MKL

Uncertain

0.91

LIST_S2

Benign

0.82

T;T

M_CAP

Benign

0.0051

MetaRNN

Benign

0.093

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.81

L;.

PrimateAI

Uncertain

0.74

PROVEAN

Benign

-0.50

N;N

REVEL

Benign

0.085

Sift

Benign

0.20

T;T

Sift4G

Uncertain

0.040

D;D

Polyphen

0.0

B;.

Vest4

0.31

MutPred

0.082

Gain of phosphorylation at P235 (P = 0.0215);.;

MVP

0.31

MPC

0.74

ClinPred

0.066

GERP RS

3.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.060

gMVP

0.47

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over