NM_013382.7:c.2111C>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_013382.7(POMT2):​c.2111C>T​(p.Ala704Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000067 in 1,492,402 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. A704A) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)
Exomes 𝑓: 0.0000067 ( 0 hom. )

Consequence

POMT2
NM_013382.7 missense

Scores

19

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: -0.848

Publications

0 publications found
Variant links:
Genes affected
POMT2 (HGNC:19743): (protein O-mannosyltransferase 2) The protein encoded by this gene is an O-mannosyltransferase that requires interaction with the product of the POMT1 gene for enzymatic function. The encoded protein is found in the membrane of the endoplasmic reticulum. Defects in this gene are a cause of Walker-Warburg syndrome (WWS).[provided by RefSeq, Oct 2008]
POMT2 Gene-Disease associations (from GenCC):
  • muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A2
    Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
  • myopathy caused by variation in POMT2
    Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
  • muscular dystrophy-dystroglycanopathy (congenital with intellectual disability), type B2
    Inheritance: AR Classification: MODERATE Submitted by: Ambry Genetics
  • autosomal recessive limb-girdle muscular dystrophy type 2N
    Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
  • congenital muscular dystrophy with cerebellar involvement
    Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
  • congenital muscular dystrophy with intellectual disability
    Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
  • muscle-eye-brain disease
    Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
  • 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: 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=0.07368451).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
POMT2NM_013382.7 linkc.2111C>T p.Ala704Val missense_variant Exon 20 of 21 ENST00000261534.9 NP_037514.2 Q9UKY4-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
POMT2ENST00000261534.9 linkc.2111C>T p.Ala704Val missense_variant Exon 20 of 21 1 NM_013382.7 ENSP00000261534.4 Q9UKY4-1

Frequencies

GnomAD3 genomes
AF:
0.00000657
AC:
1
AN:
152224
Hom.:
0
Cov.:
33
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:
0.000207
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD2 exomes
AF:
0.00000625
AC:
1
AN:
160084
AF XY:
0.00
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 FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000158
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000672
AC:
9
AN:
1340060
Hom.:
0
Cov.:
31
AF XY:
0.00000602
AC XY:
4
AN XY:
663948
show subpopulations
African (AFR)
AF:
0.0000331
AC:
1
AN:
30208
American (AMR)
AF:
0.00
AC:
0
AN:
36026
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
24854
East Asian (EAS)
AF:
0.0000281
AC:
1
AN:
35594
South Asian (SAS)
AF:
0.0000256
AC:
2
AN:
78146
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
48458
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5568
European-Non Finnish (NFE)
AF:
0.00000293
AC:
3
AN:
1025032
Other (OTH)
AF:
0.0000356
AC:
2
AN:
56174
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.492
Heterozygous variant carriers
0
1
3
4
6
7
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome 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
GnomAD4 genome
AF:
0.00000656
AC:
1
AN:
152342
Hom.:
0
Cov.:
33
AF XY:
0.0000134
AC XY:
1
AN XY:
74504
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
41572
American (AMR)
AF:
0.00
AC:
0
AN:
15304
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3472
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5184
South Asian (SAS)
AF:
0.000207
AC:
1
AN:
4834
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
10628
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
294
European-Non Finnish (NFE)
AF:
0.00
AC:
0
AN:
68030
Other (OTH)
AF:
0.00
AC:
0
AN:
2112
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.625
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
Alfa
AF:
0.00
Hom.:
0
Bravo
AF:
0.00000378
ExAC
AF:
0.0000179
AC:
2

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A2;C3150416:Muscular dystrophy-dystroglycanopathy (congenital with intellectual disability), type B2;C3150418:Autosomal recessive limb-girdle muscular dystrophy type 2N Uncertain:1
Nov 18, 2023
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 704 of the POMT2 protein (p.Ala704Val). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has not been reported in the literature in individuals affected with POMT2-related conditions. ClinVar contains an entry for this variant (Variation ID: 566007). 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 POMT2 protein function with a negative predictive value of 95%. 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
Oct 29, 2022
Revvity Omics, Revvity
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.070
BayesDel_addAF
Benign
-0.10
T
BayesDel_noAF
Benign
-0.39
CADD
Benign
0.36
DANN
Benign
0.41
DEOGEN2
Benign
0.31
T
Eigen
Benign
-1.2
Eigen_PC
Benign
-1.3
FATHMM_MKL
Benign
0.0095
N
LIST_S2
Benign
0.25
T
M_CAP
Benign
0.012
T
MetaRNN
Benign
0.074
T
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
0.14
N
PhyloP100
-0.85
PrimateAI
Benign
0.24
T
PROVEAN
Benign
0.12
N
REVEL
Benign
0.19
Sift
Benign
0.51
T
Sift4G
Benign
0.50
T
Polyphen
0.0010
B
Vest4
0.081
MutPred
0.44
Gain of catalytic residue at S708 (P = 0);
MVP
0.46
MPC
0.082
ClinPred
0.018
T
GERP RS
-2.4
Varity_R
0.024
gMVP
0.33
Mutation Taster
=98/2
polymorphism

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

Other links and lift over

dbSNP: rs746221148; hg19: chr14-77744773; API