chr3-43080270-G-A

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BS1_Supporting

The NM_032806.6(POMGNT2):​c.1162C>T​(p.Leu388Phe) variant causes a missense change. The variant allele was found at a frequency of 0.000511 in 1,614,202 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. L388L) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00030 ( 0 hom., cov: 33)
Exomes 𝑓: 0.00053 ( 0 hom. )

Consequence

POMGNT2
NM_032806.6 missense

Scores

7
11
1

Clinical Significance

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

Conservation

PhyloP100: 6.81

Publications

2 publications found
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 Gene-Disease associations (from GenCC):
  • muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type a, 8
    Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
  • myopathy caused by variation in POMGNT2
    Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
  • muscular dystrophy-dystroglycanopathy, type A
    Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -1 ACMG points.

BS1
Variant frequency is greater than expected in population nfe. GnomAdExome4 allele frequency = 0.000533 (779/1461866) while in subpopulation NFE AF = 0.000655 (728/1112000). AF 95% confidence interval is 0.000615. There are 0 homozygotes in GnomAdExome4. There are 366 alleles in the male GnomAdExome4 subpopulation. Median coverage is 37. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
POMGNT2NM_032806.6 linkc.1162C>T p.Leu388Phe missense_variant Exon 2 of 2 ENST00000344697.3 NP_116195.2 Q8NAT1A0A024R2P4
POMGNT2NM_001437285.1 linkc.1162C>T p.Leu388Phe missense_variant Exon 3 of 3 NP_001424214.1
POMGNT2XM_011534163.3 linkc.1162C>T p.Leu388Phe missense_variant Exon 3 of 3 XP_011532465.1 Q8NAT1A0A024R2P4
POMGNT2XM_017007353.2 linkc.1162C>T p.Leu388Phe missense_variant Exon 4 of 4 XP_016862842.1 Q8NAT1A0A024R2P4

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
POMGNT2ENST00000344697.3 linkc.1162C>T p.Leu388Phe missense_variant Exon 2 of 2 1 NM_032806.6 ENSP00000344125.2 Q8NAT1

Frequencies

GnomAD3 genomes
AF:
0.000302
AC:
46
AN:
152218
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.000169
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000654
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:
0.000382
Gnomad OTH
AF:
0.00144
GnomAD2 exomes
AF:
0.000334
AC:
84
AN:
251380
AF XY:
0.000324
show subpopulations
Gnomad AFR exome
AF:
0.000185
Gnomad AMR exome
AF:
0.000347
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.000545
Gnomad OTH exome
AF:
0.00114
GnomAD4 exome
AF:
0.000533
AC:
779
AN:
1461866
Hom.:
0
Cov.:
37
AF XY:
0.000503
AC XY:
366
AN XY:
727240
show subpopulations
African (AFR)
AF:
0.000119
AC:
4
AN:
33478
American (AMR)
AF:
0.000335
AC:
15
AN:
44722
Ashkenazi Jewish (ASJ)
AF:
0.0000383
AC:
1
AN:
26136
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39700
South Asian (SAS)
AF:
0.00
AC:
0
AN:
86256
European-Finnish (FIN)
AF:
0.0000374
AC:
2
AN:
53410
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5768
European-Non Finnish (NFE)
AF:
0.000655
AC:
728
AN:
1112000
Other (OTH)
AF:
0.000480
AC:
29
AN:
60396
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.490
Heterozygous variant carriers
0
49
99
148
198
247
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
28
56
84
112
140
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
GnomAD4 genome
AF:
0.000302
AC:
46
AN:
152336
Hom.:
0
Cov.:
33
AF XY:
0.000295
AC XY:
22
AN XY:
74484
show subpopulations
African (AFR)
AF:
0.000168
AC:
7
AN:
41574
American (AMR)
AF:
0.000653
AC:
10
AN:
15308
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3472
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5178
South Asian (SAS)
AF:
0.00
AC:
0
AN:
4828
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
10624
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
294
European-Non Finnish (NFE)
AF:
0.000382
AC:
26
AN:
68036
Other (OTH)
AF:
0.00142
AC:
3
AN:
2112
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.514
Heterozygous variant carriers
0
3
6
9
12
15
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome Het
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
Alfa
AF:
0.000501
Hom.:
1
Bravo
AF:
0.000359
TwinsUK
AF:
0.00
AC:
0
ALSPAC
AF:
0.000778
AC:
3
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.00105
AC:
9
ExAC
AF:
0.000296
AC:
36
EpiCase
AF:
0.000600
EpiControl
AF:
0.000356

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Uncertain:2
Mar 01, 2023
Revvity Omics, Revvity
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Sep 02, 2022
GeneDx
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Inborn genetic diseases Uncertain:1
Oct 06, 2021
Ambry Genetics
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

The c.1162C>T (p.L388F) alteration is located in exon 2 (coding exon 1) of the POMGNT2 gene. This alteration results from a C to T substitution at nucleotide position 1162, causing the leucine (L) at amino acid position 388 to be replaced by a phenylalanine (F). 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
Oct 13, 2022
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This sequence change replaces leucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 388 of the POMGNT2 protein (p.Leu388Phe). This variant is present in population databases (rs139060322, gnomAD 0.05%). 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: 473272). 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. 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. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
0.55
BayesDel_addAF
Pathogenic
0.19
D
BayesDel_noAF
Pathogenic
0.39
CADD
Pathogenic
28
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.68
D;D
Eigen
Pathogenic
0.88
Eigen_PC
Pathogenic
0.84
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Uncertain
0.96
.;D
M_CAP
Uncertain
0.11
D
MetaRNN
Uncertain
0.50
T;T
MetaSVM
Uncertain
0.62
D
MutationAssessor
Pathogenic
3.4
M;M
PhyloP100
6.8
PrimateAI
Uncertain
0.62
T
PROVEAN
Uncertain
-2.6
D;D
REVEL
Pathogenic
0.76
Sift
Uncertain
0.0010
D;D
Sift4G
Uncertain
0.0060
D;D
Polyphen
1.0
D;D
Vest4
0.60
MVP
0.83
MPC
0.96
ClinPred
0.25
T
GERP RS
5.5
Varity_R
0.60
gMVP
0.76
Mutation Taster
=41/59
disease causing

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

Other links and lift over

dbSNP: rs139060322; hg19: chr3-43121762; COSMIC: COSV99048909; API