16-8797943-C-G

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1PM2PP3_StrongPP5_Moderate

The NM_000303.3(PMM2):ā€‹c.61C>Gā€‹(p.Arg21Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000156 in 1,605,426 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (ā˜…).

Frequency

Genomes: š‘“ 0.000013 ( 0 hom., cov: 33)
Exomes š‘“: 0.000016 ( 0 hom. )

Consequence

PMM2
NM_000303.3 missense

Scores

12
6
1

Clinical Significance

Likely pathogenic criteria provided, single submitter P:3

Conservation

PhyloP100: 1.66
Variant links:
Genes affected
PMM2 (HGNC:9115): (phosphomannomutase 2) The protein encoded by this gene catalyzes the isomerization of mannose 6-phosphate to mannose 1-phosphate, which is a precursor to GDP-mannose necessary for the synthesis of dolichol-P-oligosaccharides. Mutations in this gene have been shown to cause defects in glycoprotein biosynthesis, which manifests as carbohydrate-deficient glycoprotein syndrome type I. [provided by RefSeq, Jul 2008]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 10 ACMG points.

PM1
In a binding_site (size 0) in uniprot entity PMM2_HUMAN
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.962
PP5
Variant 16-8797943-C-G is Pathogenic according to our data. Variant chr16-8797943-C-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1284906.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-8797943-C-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
PMM2NM_000303.3 linkuse as main transcriptc.61C>G p.Arg21Gly missense_variant 1/8 ENST00000268261.9 NP_000294.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
PMM2ENST00000268261.9 linkuse as main transcriptc.61C>G p.Arg21Gly missense_variant 1/81 NM_000303.3 ENSP00000268261 P1O15305-1

Frequencies

GnomAD3 genomes
AF:
0.0000131
AC:
2
AN:
152220
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.0000241
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
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:
0.0000147
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.00000442
AC:
1
AN:
226464
Hom.:
0
AF XY:
0.00
AC XY:
0
AN XY:
123786
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:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00000988
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000158
AC:
23
AN:
1453206
Hom.:
0
Cov.:
32
AF XY:
0.0000152
AC XY:
11
AN XY:
722208
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:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000198
Gnomad4 OTH exome
AF:
0.0000167
GnomAD4 genome
AF:
0.0000131
AC:
2
AN:
152220
Hom.:
0
Cov.:
33
AF XY:
0.0000134
AC XY:
1
AN XY:
74356
show subpopulations
Gnomad4 AFR
AF:
0.0000241
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000147
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000279
Hom.:
0
Bravo
AF:
0.0000264
ExAC
AF:
0.00000830
AC:
1

ClinVar

Significance: Likely pathogenic
Submissions summary: Pathogenic:3
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not provided Pathogenic:2
Pathogenic, no assertion criteria providedclinical testingGenome Diagnostics Laboratory, University Medical Center Utrecht-- -
Pathogenic, no assertion criteria providedclinical testingClinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center-- -
PMM2-congenital disorder of glycosylation Pathogenic:1
Likely pathogenic, criteria provided, single submitterclinical testingBaylor GeneticsMar 12, 2024- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.95
BayesDel_addAF
Pathogenic
0.53
D
BayesDel_noAF
Pathogenic
0.53
CADD
Pathogenic
29
DANN
Uncertain
1.0
DEOGEN2
Pathogenic
0.90
D;.
Eigen
Uncertain
0.57
Eigen_PC
Uncertain
0.52
FATHMM_MKL
Uncertain
0.80
D
LIST_S2
Uncertain
0.97
D;D
M_CAP
Pathogenic
0.34
D
MetaRNN
Pathogenic
0.96
D;D
MetaSVM
Pathogenic
1.1
D
MutationAssessor
Pathogenic
3.1
M;.
MutationTaster
Benign
1.0
D;D;D;D;N
PrimateAI
Uncertain
0.73
T
PROVEAN
Pathogenic
-5.5
D;D
REVEL
Pathogenic
0.90
Sift
Pathogenic
0.0
D;D
Sift4G
Pathogenic
0.0
D;D
Polyphen
0.99
D;.
Vest4
0.83
MutPred
0.83
Gain of methylation at K23 (P = 0.0705);Gain of methylation at K23 (P = 0.0705);
MVP
0.95
MPC
0.024
ClinPred
1.0
D
GERP RS
4.8
Varity_R
0.97
gMVP
0.78

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: rs758340382; hg19: chr16-8891800; API