1-154959311-G-A

Variant names:

• chr1-154959311-G-A
• rs776756862
• NM_138300.4:c.689C>T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_138300.4(PYGO2):​c.689C>T​(p.Pro230Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000138 in 1,445,674 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: PYGO2 NM_138300.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.92

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.20103765).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PYGO2	NM_138300.4	c.689C>T	p.Pro230Leu	missense_variant	Exon 3 of 3	ENST00000368457.3	NP_612157.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PYGO2	ENST00000368457.3	c.689C>T	p.Pro230Leu	missense_variant	Exon 3 of 3	1	NM_138300.4	ENSP00000357442.2
PYGO2	ENST00000368456.1	c.578C>T	p.Pro193Leu	missense_variant	Exon 3 of 3	2		ENSP00000357441.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000128 AC: 3 AN: 234278 Hom.: 0 AF XY: 0.00000787 AC XY: 1 AN XY: 127028

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000170

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000138 AC: 2 AN: 1445674 Hom.: 0 Cov.: 32 AF XY: 0.00000139 AC XY: 1 AN XY: 718796

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000505

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.0000264

ExAC AF: 0.0000165 AC: 2

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Feb 22, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.689C>T (p.P230L) 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 689, causing the proline (P) at amino acid position 230 to be replaced by a leucine (L). 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	0.15
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.34
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.37	T;.
Eigen	Benign	0.13
Eigen_PC	Uncertain	0.23
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.85	T;T
M_CAP	Benign	0.0039	T
MetaRNN	Benign	0.20	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.97	L;.
PrimateAI	Pathogenic	0.79	T
PROVEAN	Benign	-0.87	N;N
REVEL	Benign	0.12
Sift	Benign	0.22	T;T
Sift4G	Benign	0.29	T;T
Polyphen		0.89	P;.
Vest4		0.45
MutPred		0.12		Loss of glycosylation at S225 (P = 0.122);.;
MVP		0.40
MPC		0.78
ClinPred		0.20	T
GERP RS		4.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.12
gMVP		0.34

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

Other links and lift over

dbSNP: rs776756862; hg19: chr1-154931787;