rs139716296

chr16-8804845-T-Cchr16-8804845-T-G

Variant summary

Our verdict is Pathogenic. Variant got 20 ACMG points: 20P and 0B. PVS1 PM2 PP3_Moderate PP5_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
• Scores: Splicing: ADA: 0.9482
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:14
• 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]

ACMG classification

Verdict is Pathogenic. Variant got 20 ACMG points.

• PVS1: Splicing 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
• PP3: BayesDel_addAF computational evidence supports a deleterious effect, 0.42
• 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	UniProt
PMM2	NM_000303.3	c.255+2T>C		splice_donor_variant		ENST00000268261.9
PMM2	XM_047434215.1	c.7-1471T>C		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PMM2	ENST00000268261.9	c.255+2T>C		splice_donor_variant		1	NM_000303.3	P1

Frequencies

GnomAD3 genomes AF: 0.0000658 AC: 10 AN: 152010 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000242

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: 0.000132

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000676 AC: 17 AN: 251324 Hom.: 0 AF XY: 0.0000589 AC XY: 8 AN XY: 135856

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000145

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: 0.0000968

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000938 AC: 135 AN: 1439616 Hom.: 0 Cov.: 27 AF XY: 0.0000920 AC XY: 66 AN XY: 717778

Gnomad4 AFR exome AF: 0.0000908

Gnomad4 AMR exome AF: 0.000112

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000233

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000113

Gnomad4 OTH exome AF: 0.0000335

GnomAD4 genome AF: 0.0000658 AC: 10 AN: 152010 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74244

Gnomad4 AFR AF: 0.0000242

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: 0.000132

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000124 Hom.: 0

Bravo AF: 0.0000945

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.0000824 AC: 10

EpiCase AF: 0.000109

EpiControl AF: 0.000178

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:14

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

PMM2-congenital disorder of glycosylation Pathogenic:9

Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Oct 03, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	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	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	Revvity Omics, Revvity	Jun 21, 2021	- -
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	Fulgent Genetics, Fulgent Genetics	Oct 31, 2018	- -
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. -

not provided Pathogenic:3

Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
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) -

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

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.42	D
BayesDel_noAF	Uncertain	0.13
Cadd	Pathogenic	27
Dann	Uncertain	0.99
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.86
FATHMM_MKL	Pathogenic	0.99	D
MutationTaster	Benign	1.0	D;D;D;D;D
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.95
dbscSNV1_RF	Benign	0.68
SpliceAI score (max)		0.96		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.96		Position offset: -2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs139716296; hg19: chr16-8898702;