Genetic Variant PAGE2B:p.Pro23Ala (chrX-55076108-C-G) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_001015038.3(PAGE2B):c.67C>G(p.Pro23Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000581 in 1,204,715 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 3 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000090 ( 0 hom., 1 hem., cov: 22)

Exomes 𝑓: 0.0000055 ( 0 hom. 2 hem. )

Consequence

PAGE2B
NM_001015038.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -2.36

Variant links:

Genes affected

PAGE2B (HGNC:31805): (PAGE family member 2B)

PAGE2B links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.058801502).

BS2

High Hemizygotes in GnomAdExome4 at 2 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PAGE2B	NM_001015038.3 link	c.67C>G	p.Pro23Ala	missense_variant	Exon 2 of 5	ENST00000374971.2	NP_001015038.1	Q5JRK9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PAGE2B	ENST00000374971.2 link	c.67C>G	p.Pro23Ala	missense_variant	Exon 2 of 5	1	NM_001015038.3	ENSP00000364110.1		Q5JRK9
PAGE2B	ENST00000374974.7 link	c.67C>G	p.Pro23Ala	missense_variant	Exon 2 of 5	5		ENSP00000364113.3		Q5JRL0

Frequencies

GnomAD3 genomes

AF:

0.00000900

AC:

AN:

111136

Hom.:

Cov.:

AF XY:

0.0000300

AC XY:

AN XY:

33332

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000377

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000110

AC:

AN:

181959

Hom.:

AF XY:

0.0000150

AC XY:

AN XY:

66563

show subpopulations

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 SAS exome

AF:

0.000108

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000549

AC:

AN:

1093524

Hom.:

Cov.:

AF XY:

0.00000556

AC XY:

AN XY:

359418

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000930

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.0000218

GnomAD4 genome

AF:

0.00000899

AC:

AN:

111191

Hom.:

Cov.:

AF XY:

0.0000299

AC XY:

AN XY:

33397

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000378

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

ExAC

AF:

0.0000247

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Feb 23, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.67C>G (p.P23A) alteration is located in exon 2 (coding exon 1) of the PAGE2B gene. This alteration results from a C to G substitution at nucleotide position 67, causing the proline (P) at amino acid position 23 to be replaced by an alanine (A). 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

0.070

BayesDel_addAF

Benign

-0.75

BayesDel_noAF

Benign

-1.1

CADD

Benign

0.013

DANN

Benign

0.27

DEOGEN2

Benign

0.012

.;T

FATHMM_MKL

Benign

0.00054

LIST_S2

Benign

0.62

T;T

M_CAP

Benign

0.0012

MetaRNN

Benign

0.059

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.5

.;L

PrimateAI

Benign

0.39

PROVEAN

Uncertain

-2.7

D;D

REVEL

Benign

0.073

Sift

Benign

0.081

T;T

Sift4G

Benign

1.0

T;T

Polyphen

0.66

.;P

Vest4

0.051

MutPred

0.58

Gain of MoRF binding (P = 0.0987);Gain of MoRF binding (P = 0.0987);

MVP

0.014

MPC

0.94

ClinPred

0.25

GERP RS

-1.2

Varity_R

0.041

gMVP

0.0068

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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