rs143667339

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 2P and 3B. PM2BP4_ModerateBS1_Supporting

The NM_032806.6(POMGNT2):c.77G>A(p.Arg26His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000246 in 1,608,882 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R26C) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00024 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00025 ( 0 hom. )

Consequence

POMGNT2
NM_032806.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:4

Conservation

PhyloP100: 3.20

Variant links:

Genes affected

POMGNT2 (HGNC:25902): (protein O-linked mannose N-acetylglucosaminyltransferase 2 (beta 1,4-)) This gene encodes a protein with glycosyltransferase activity although its function is not currently known. [provided by RefSeq, Sep 2012]

POMGNT2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.08140865).

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000237 (36/152172) while in subpopulation NFE AF= 0.000441 (30/68022). AF 95% confidence interval is 0.000317. There are 0 homozygotes in gnomad4. There are 17 alleles in male gnomad4 subpopulation. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
POMGNT2	NM_032806.6 linkuse as main transcript	c.77G>A	p.Arg26His	missense_variant	2/2	ENST00000344697.3
POMGNT2	XM_005265515.4 linkuse as main transcript	c.77G>A	p.Arg26His	missense_variant	3/3
POMGNT2	XM_011534163.3 linkuse as main transcript	c.77G>A	p.Arg26His	missense_variant	3/3
POMGNT2	XM_017007353.2 linkuse as main transcript	c.77G>A	p.Arg26His	missense_variant	4/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
POMGNT2	ENST00000344697.3 linkuse as main transcript	c.77G>A	p.Arg26His	missense_variant	2/2	1	NM_032806.6	P1

Frequencies

GnomAD3 genomes

AF:

0.000237

AC:

AN:

152172

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000965

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:

0.000441

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000218

AC:

AN:

242882

Hom.:

AF XY:

0.000249

AC XY:

AN XY:

132500

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000584

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000659

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000434

Gnomad OTH exome

AF:

0.000168

GnomAD4 exome

AF:

0.000246

AC:

359

AN:

1456710

Hom.:

Cov.:

AF XY:

0.000252

AC XY:

183

AN XY:

724846

show subpopulations

Gnomad4 AFR exome

AF:

0.0000896

Gnomad4 AMR exome

AF:

0.0000448

Gnomad4 ASJ exome

AF:

0.0000384

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000813

Gnomad4 FIN exome

AF:

0.0000203

Gnomad4 NFE exome

AF:

0.000301

Gnomad4 OTH exome

AF:

0.0000830

GnomAD4 genome

AF:

0.000237

AC:

AN:

152172

Hom.:

Cov.:

AF XY:

0.000229

AC XY:

AN XY:

74330

show subpopulations

Gnomad4 AFR

AF:

0.0000965

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:

0.000441

Gnomad4 OTH

AF:

0.000478

Alfa

AF:

0.000306

Hom.:

Bravo

AF:

0.000215

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000698

AC:

ExAC

AF:

0.000198

AC:

EpiCase

AF:

0.000545

EpiControl

AF:

0.000771

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type a, 8

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Dec 22, 2023	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 26 of the POMGNT2 protein (p.Arg26His). This variant is present in population databases (rs143667339, gnomAD 0.04%). This variant has not been reported in the literature in individuals affected with POMGNT2-related conditions. ClinVar contains an entry for this variant (Variation ID: 393196). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt POMGNT2 protein function with a negative predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Aug 29, 2019	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 27, 2021

The c.77G>A (p.R26H) alteration is located in exon 2 (coding exon 1) of the POMGNT2 gene. This alteration results from a G to A substitution at nucleotide position 77, causing the arginine (R) at amino acid position 26 to be replaced by a histidine (H). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Jul 25, 2023

In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.24

BayesDel_noAF

Benign

-0.27

Cadd

Benign

Dann

Uncertain

1.0

DEOGEN2

Benign

0.0098

T;T

Eigen

Benign

-0.29

Eigen_PC

Benign

-0.17

FATHMM_MKL

Uncertain

0.91

M_CAP

Benign

0.060

MetaRNN

Benign

0.081

T;T

MetaSVM

Benign

-0.66

MutationAssessor

Benign

1.4

L;L

MutationTaster

Benign

0.67

N;N

PrimateAI

Benign

0.44

PROVEAN

Benign

-0.12

N;N

REVEL

Benign

0.15

Sift

Uncertain

0.014

D;D

Sift4G

Benign

0.19

T;T

Polyphen

0.0030

B;B

Vest4

0.20

MVP

0.63

MPC

0.57

ClinPred

0.058

GERP RS

3.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.6

Varity_R

0.033

gMVP

0.49

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