rs139716296
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Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000303.3(PMM2):c.255+2T>C variant causes a splice donor change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000911 in 1,591,626 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Pathogenic (★★).
Frequency
Genomes: 𝑓 0.000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000094 ( 0 hom. )
Consequence
PMM2
NM_000303.3 splice_donor
NM_000303.3 splice_donor
Scores
4
2
1
Splicing: ADA: 0.9482
2
Clinical Significance
Conservation
PhyloP100: 7.49
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]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 18 ACMG points.
PVS1
Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, Cryptic splice site detected, with MaxEntScore 3.3, offset of 4, new splice context is: cagGTtctt. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 16-8804845-T-C is Pathogenic according to our data. Variant chr16-8804845-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 321216.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-8804845-T-C is described in Lovd as [Pathogenic].
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| PMM2 | NM_000303.3 | c.255+2T>C | splice_donor_variant | ENST00000268261.9 | NP_000294.1 | |||
| PMM2 | XM_047434215.1 | c.7-1471T>C | intron_variant | XP_047290171.1 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| PMM2 | ENST00000268261.9 | c.255+2T>C | splice_donor_variant | 1 | NM_000303.3 | ENSP00000268261 | P1 |
Frequencies
GnomAD3 genomes 0.0000658 AC: 10AN: 152010Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000676 AC: 17AN: 251324Hom.: 0 AF XY: 0.0000589 AC XY: 8AN XY: 135856
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GnomAD4 exome AF: 0.0000938 AC: 135AN: 1439616Hom.: 0 Cov.: 27 AF XY: 0.0000920 AC XY: 66AN XY: 717778
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GnomAD4 genome 0.0000658 AC: 10AN: 152010Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74244
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:14
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
PMM2-congenital disorder of glycosylation Pathogenic:9
| Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 25, 2024 | - - |
| Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 16, 2020 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 30, 2024 | This sequence change affects a donor splice site in intron 3 of the PMM2 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in PMM2 are known to be pathogenic (PMID: 19862844). This variant is present in population databases (rs139716296, gnomAD 0.01%). Disruption of this splice site has been observed in individuals with PMM2-related congenital disorder of glycosylation (PMM2-CDG) (PMID: 11156536, 15844218, 18948042, 23806237). This variant is also known as IVS3+2C>T. ClinVar contains an entry for this variant (Variation ID: 321216). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 27, 2017 | The PMM2 c.255+2T>C variant, also known as IVS3+2T>C, occurs in a canonical splice site (donor) and is therefore predicted to disrupt or distort the normal gene product. The c.255+2T>C variant has been reported in eight studies in which it is found in at least seven affected individuals, including two siblings, in a compound heterozygous state with another missense variant, and in one individual with unspecified zygosity (Matthijs et al. 1999; Grünewald et al. 2001; Briones et al. 2002; Le Bizec et al. 2005; Pérez-Dueñas et al. 2009; Pérez et al. 2011; Jones et al. 2013; Monin et al. 2014). Control data are unavailable for this variant, which is reported at a frequency of 0.00011 in the European (non-Finnish) population of the Exome Aggregation Consortium. The phosphomannomutase activity in fibroblasts and leukocytes from patients with the variant was significantly reduced compared to normal (Grunewald et al. 2001; Perez-Duenas et al. 2009). Based on the evidence, the c.255+2T>C variant is classified as pathogenic for congenital disorders of glycosylation. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Oct 01, 2021 | NM_000303.2(PMM2):c.255+2T>C is a canonical splice variant classified as pathogenic in the context of congenital disorder of glycosylation type Ia. c.255+2T>C has been observed in cases with relevant disease (PMID: 12705494, 15844218). Functional assessments of this variant are not available in the literature. c.255+2T>C has been observed in population frequency databases (gnomAD: AMR 0.01%). In summary, NM_000303.2(PMM2):c.255+2T>C is a canonical splice variant in a gene where loss of function is a known mechanism of disease, is predicted to disrupt protein function, and has been observed more frequently in cases with the relevant disease than in healthy populations. Please note: this variant was assessed in the context of healthy population screening. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Johns Hopkins Genomics, Johns Hopkins University | May 19, 2020 | This PMM2 variant is predicted to destroy the native canonical splice donor site in exon 2. PMM2 c.255+2T>C has been reported in an individual with congenital disorder of glycosylation. This variant (rs139716296) is rare (<0.1%) in a large population dataset (gnomAD: 19/282690 total alleles; 0.007%; no homozygotes) and has been reported in ClinVar. We consider this variant to be pathogenic. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | May 11, 2018 | Variant summary: PMM2 c.255+2T>C is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes a 5 splicing donor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 6.5e-05 in 277094 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in PMM2 causing Congenital Disorder of Glycosylation Type 1a (6.5e-05 vs 0.0056), allowing no conclusion about variant significance. The variant, c.255+2T>C, has been reported in the literature in multiple individuals from families affected with Congenital Disorder of Glycosylation Type 1a (Grunewald_2001, Jones_2013, Le Bizec_2005, Monin_2014). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function (Grunewald_2001). The most pronounced variant effect results in 10%-<30% of normal activity. Multiple ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cites the variant as "likely pathogenic." Based on the evidence outlined above, the variant was classified as pathogenic. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Oct 31, 2018 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Jun 21, 2021 | - - |
not provided Pathogenic:3
| Pathogenic, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Dec 06, 2021 | Identified in other patients with congenital disorders of glycosylation in published literature (Jones et al., 2013; Matthijs et al., 1999); Canonical splice site variant predicted to result in a null allele in a gene for which loss-of-function is a known mechanism of disease; Not observed at a significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 25497157, 25525159, 23430838, 28139241, 23806237, 31980526, 31589614, 34277356, 18948042, 12705494, 11156536, 15844218, 10527672) - |
| Pathogenic, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
Inborn genetic diseases Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Mar 25, 2021 | The c.255+2T>C intronic variant results from a T to C substitution two nucleotides after coding exon 3 of the PMM2 gene. Alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. Based on data from the Genome Aggregation Database (gnomAD) database, the PMM2 c.255+2T>C alteration was observed in 0.01% (19/282690) of total alleles studied, with a frequency of 0.01% (5/35424) in the Latino subpopulation. This mutation (also known as IVS3+2C>T in the literature) has been detected as compound heterozygous with a second PMM2 mutation in many individuals with congenital disorder of glycosylation 1A (Hou, 2020; Matthijs,1999; Grünewald, 2001; Briones, 2002). This nucleotide position is highly conserved in available vertebrate species. This mutation was shown to significantly impact phosphomannomutase activity in fibroblasts and leukocytes compared to wild type (Grünewald, 2001). In silico splice site analysis predicts that this alteration will weaken the native splice donor site. Based on the available evidence, this alteration is classified as pathogenic. - |
Intellectual disability Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Diagnostic Laboratory, Strasbourg University Hospital | Apr 20, 2020 | - - |
Computational scores
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Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Uncertain
CADD
Pathogenic
DANN
Uncertain
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
MutationTaster
Benign
D;D;D;D;D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Splicing
Name
Calibrated prediction
Score
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dbscSNV1_ADA
Benign
dbscSNV1_RF
Benign
SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_DL_spliceai
Position offset: -2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at