NM_000303.3:c.205C>T

Variant names:

• chr16-8804793-C-T
• rs769648248
• NM_000303.3:c.205C>T

Variant summary

Our verdict is Pathogenic. The variant received 17 ACMG points: 17P and 0B. PM1 PM2 PM5 PP2 PP3_Moderate PP5_Very_Strong

The NM_000303.3(PMM2):​c.205C>T​(p.Pro69Ser) variant causes a missense change. The variant allele was found at a frequency of 0.0000246 in 1,461,054 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P69T) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000025 (0 hom.)
• Consequence: PMM2 NM_000303.3 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:8
• Conservation: PhyloP100: 3.94
• Publications: 7 publications found

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]

PMM2 Gene-Disease associations (from GenCC):

• congenital disorder of glycosylation type I

  Inheritance: AR Classification: DEFINITIVE Submitted by: Myriad Women’s Health
• PMM2-congenital disorder of glycosylation

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, G2P, ClinGen, Labcorp Genetics (formerly Invitae)
• hyperinsulinemic hypoglycemia with polycystic kidney disease

  Inheritance: AR Classification: MODERATE Submitted by: ClinGen

ACMG classification

Our verdict: Pathogenic. The variant received 17 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in NM_000303.3
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr16-8804793-C-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 2119757.
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 89 curated pathogenic missense variants (we use a threshold of 10). The gene has 24 curated benign missense variants. Gene score misZ: -1.3872 (below the threshold of 3.09). Trascript score misZ: -1.8083 (below the threshold of 3.09). GenCC associations: The gene is linked to PMM2-congenital disorder of glycosylation, congenital disorder of glycosylation type I.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.849
• PP5: Variant 16-8804793-C-T is Pathogenic according to our data. Variant chr16-8804793-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 371307.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000303.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PMM2	NM_000303.3	MANE Select	c.205C>T	p.Pro69Ser	missense	Exon 3 of 8	NP_000294.1	A0A0S2Z4J6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PMM2	ENST00000268261.9	TSL:1 MANE Select	c.205C>T	p.Pro69Ser	missense	Exon 3 of 8	ENSP00000268261.4	O15305-1
	PMM2	ENST00000565221.5	TSL:1	n.178+2883C>T		intron	N/A	ENSP00000457932.1	H3BV34
	PMM2	ENST00000566540.5	TSL:1	n.179-1523C>T		intron	N/A	ENSP00000454284.1	H3BM92

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.0000246 AC: 36 AN: 1461054 Hom.: 0 Cov.: 29 AF XY: 0.0000275 AC XY: 20 AN XY: 726866

African (AFR) AF: 0.00 AC: 0 AN: 33466

American (AMR) AF: 0.00 AC: 0 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26124

East Asian (EAS) AF: 0.00 AC: 0 AN: 39676

South Asian (SAS) AF: 0.00 AC: 0 AN: 86250

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53412

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5762

European-Non Finnish (NFE) AF: 0.0000324 AC: 36 AN: 1111282

Other (OTH) AF: 0.00 AC: 0 AN: 60362

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
6	-	-	PMM2-congenital disorder of glycosylation (6)
1	-	-	Inborn genetic diseases (1)
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.27
BayesDel_addAF	Pathogenic	0.31	D
BayesDel_noAF	Pathogenic	0.21
CADD	Benign	20
DANN	Benign	0.31
DEOGEN2	Uncertain	0.49	T
Eigen	Benign	-0.33
Eigen_PC	Benign	-0.073
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Benign	0.85	D
M_CAP	Benign	0.048	D
MetaRNN	Pathogenic	0.85	D
MetaSVM	Uncertain	0.10	D
MutationAssessor	Benign	0.39	N
PhyloP100		3.9
PrimateAI	Benign	0.45	T
PROVEAN	Benign	0.97	N
REVEL	Uncertain	0.50
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.028	B
Vest4		0.78
MutPred		0.87		Gain of sheet (P = 0.1208)
MVP		0.87
MPC		0.010
ClinPred		0.90	D
GERP RS		4.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.47
gMVP		0.88
Mutation Taster		=24/76	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		3.0
SpliceAI score (max)		0.47		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.47		Position offset: -26

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

Other links and lift over

dbSNP: rs769648248; hg19: chr16-8898650;