3-43080782-C-T

Variant summary

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

The NM_032806.6(POMGNT2):​c.650G>A​(p.Arg217Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000489 in 1,613,906 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.00012 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000041 ( 0 hom. )

Consequence

POMGNT2
NM_032806.6 missense

Scores

3
16

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: 2.61
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]

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=0.13677505).
BS1
Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000125 (19/152170) while in subpopulation AFR AF= 0.000434 (18/41438). AF 95% confidence interval is 0.00028. There are 0 homozygotes in gnomad4. There are 8 alleles in male gnomad4 subpopulation. Median coverage is 33. 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 Protein UniProt
POMGNT2NM_032806.6 linkuse as main transcriptc.650G>A p.Arg217Gln missense_variant 2/2 ENST00000344697.3 NP_116195.2 Q8NAT1A0A024R2P4
POMGNT2XM_005265515.4 linkuse as main transcriptc.650G>A p.Arg217Gln missense_variant 3/3 XP_005265572.1 Q8NAT1A0A024R2P4
POMGNT2XM_011534163.3 linkuse as main transcriptc.650G>A p.Arg217Gln missense_variant 3/3 XP_011532465.1 Q8NAT1A0A024R2P4
POMGNT2XM_017007353.2 linkuse as main transcriptc.650G>A p.Arg217Gln missense_variant 4/4 XP_016862842.1 Q8NAT1A0A024R2P4

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
POMGNT2ENST00000344697.3 linkuse as main transcriptc.650G>A p.Arg217Gln missense_variant 2/21 NM_032806.6 ENSP00000344125.2 Q8NAT1

Frequencies

GnomAD3 genomes
AF:
0.000125
AC:
19
AN:
152170
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.000434
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.000207
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000399
AC:
10
AN:
250662
Hom.:
0
AF XY:
0.0000295
AC XY:
4
AN XY:
135662
show subpopulations
Gnomad AFR exome
AF:
0.000313
Gnomad AMR exome
AF:
0.0000289
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.0000327
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000177
Gnomad OTH exome
AF:
0.000163
GnomAD4 exome
AF:
0.0000410
AC:
60
AN:
1461736
Hom.:
0
Cov.:
37
AF XY:
0.0000413
AC XY:
30
AN XY:
727168
show subpopulations
Gnomad4 AFR exome
AF:
0.000657
Gnomad4 AMR exome
AF:
0.0000224
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000252
Gnomad4 SAS exome
AF:
0.0000696
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000144
Gnomad4 OTH exome
AF:
0.000166
GnomAD4 genome
AF:
0.000125
AC:
19
AN:
152170
Hom.:
0
Cov.:
33
AF XY:
0.000108
AC XY:
8
AN XY:
74336
show subpopulations
Gnomad4 AFR
AF:
0.000434
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.000207
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000999
Hom.:
0
Bravo
AF:
0.000113
ESP6500AA
AF:
0.000454
AC:
2
ESP6500EA
AF:
0.00
AC:
0
ExAC
AF:
0.0000412
AC:
5
Asia WGS
AF:
0.000577
AC:
2
AN:
3478
EpiCase
AF:
0.00
EpiControl
AF:
0.0000593

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsSep 24, 2024The c.650G>A (p.R217Q) 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 650, causing the arginine (R) at amino acid position 217 to be replaced by a glutamine (Q). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -
Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type a, 8 Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 19, 2024This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 217 of the POMGNT2 protein (p.Arg217Gln). This variant is present in population databases (rs368280765, 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: 449180). 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. -
not provided Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingGeneDxDec 13, 2024In silico analysis indicates 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
0.14
BayesDel_addAF
Benign
-0.22
T
BayesDel_noAF
Benign
-0.25
CADD
Uncertain
24
DANN
Uncertain
1.0
DEOGEN2
Benign
0.16
T;T
Eigen
Benign
-0.031
Eigen_PC
Benign
0.094
FATHMM_MKL
Uncertain
0.85
D
LIST_S2
Uncertain
0.95
.;D
M_CAP
Benign
0.029
D
MetaRNN
Benign
0.14
T;T
MetaSVM
Benign
-0.52
T
MutationAssessor
Benign
1.9
M;M
PrimateAI
Benign
0.40
T
PROVEAN
Benign
-0.10
N;N
REVEL
Benign
0.17
Sift
Benign
0.080
T;T
Sift4G
Benign
0.12
T;T
Polyphen
0.26
B;B
Vest4
0.34
MVP
0.74
MPC
0.62
ClinPred
0.023
T
GERP RS
4.8
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.082
gMVP
0.65

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.

Other links and lift over

dbSNP: rs368280765; hg19: chr3-43122274; COSMIC: COSV60953095; API