chr1-154959421-C-A

Variant names:

• chr1-154959421-C-A
• rs1299232187
• NM_138300.4:c.579G>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_138300.4(PYGO2):​c.579G>T​(p.Met193Ile) variant causes a missense change. The variant allele was found at a frequency of 0.00000071 in 1,408,840 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
• Consequence: PYGO2 NM_138300.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.11
• Publications: 0 publications found

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]

ENSG00000310191 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.15813977).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_138300.4. 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
	PYGO2	NM_138300.4	MANE Select	c.579G>T	p.Met193Ile	missense	Exon 3 of 3	NP_612157.1	Q9BRQ0

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PYGO2	ENST00000368457.3	TSL:1 MANE Select	c.579G>T	p.Met193Ile	missense	Exon 3 of 3	ENSP00000357442.2	Q9BRQ0
	PYGO2	ENST00000368456.1	TSL:2	c.468G>T	p.Met156Ile	missense	Exon 3 of 3	ENSP00000357441.1	Q5T171
	ENSG00000310191	ENST00000848032.1		n.424-1460C>A		intron	N/A

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000491 AC: 1 AN: 203792 AF XY: 0.00000912

Gnomad AFR exome AF: 0.00

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: 0.0000104

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 7.10e-7 AC: 1 AN: 1408840 Hom.: 0 Cov.: 31 AF XY: 0.00000143 AC XY: 1 AN XY: 697298

African (AFR) AF: 0.00 AC: 0 AN: 31232

American (AMR) AF: 0.00 AC: 0 AN: 34038

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22544

East Asian (EAS) AF: 0.00 AC: 0 AN: 39030

South Asian (SAS) AF: 0.00 AC: 0 AN: 78326

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51936

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5524

European-Non Finnish (NFE) AF: 9.19e-7 AC: 1 AN: 1088284

Other (OTH) AF: 0.00 AC: 0 AN: 57926

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.59
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	19
DANN	Benign	0.92
DEOGEN2	Benign	0.29	T
Eigen	Benign	-0.26
Eigen_PC	Benign	-0.066
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.69	T
M_CAP	Benign	0.0034	T
MetaRNN	Benign	0.16	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.97	L
PhyloP100		4.1
PrimateAI	Uncertain	0.62	T
PROVEAN	Benign	-0.87	N
REVEL	Benign	0.048
Sift	Benign	0.72	T
Sift4G	Benign	0.57	T
Polyphen		0.0	B
Vest4		0.46
MutPred		0.27		Gain of catalytic residue at S195 (P = 0.2172)
MVP		0.19
MPC		0.30
ClinPred		0.27	T
GERP RS		4.1
Varity_R		0.16
gMVP		0.18
Mutation Taster		=83/17	polymorphism

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

Other links and lift over

dbSNP: rs1299232187; hg19: chr1-154931897; COSMIC: COSV63757283; COSMIC: COSV63757283;