chr16-8847805-T-A

Variant names:

• chr16-8847805-T-A
• NM_000303.3:c.721T>A
• PMM2 p.Cys241Ser

GermlineCancer (beta)

Variant summary

Our verdict is Pathogenic.

>+14 Pathogenic

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 18 classification points (ACMG Germline Pathogenicity v2019). PS1_Very_StrongPM1PM2PM5PP3_Strong

The NM_000303.3(PMM2):c.721T>A (p.Cys241Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant is absent from the gnomAD population database at sites with sufficient sequencing coverage. In-silico predictor (REVEL) classifies this variant as likely damaging/oncogenic. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. A different missense at the same amino acid position has been reported as Pathogenic/Likely Pathogenic in ClinVar: p.C241R: Likely_pathogenic (ClinVar VariationId 2847057, 1 star) This exact variant is curated in the UniProt human variants database as Uncertain Significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: PMM2 NM_000303.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.96
• Publications: 0 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: G2P, Labcorp Genetics (formerly Invitae), Natera, PanelApp Australia, Orphanet, ClinGen
• hyperinsulinemic hypoglycemia with polycystic kidney disease

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: PanelApp Australia, ClinGen

ENSG00000260350 (HGNC:58482): ()

Classification according to ACMG Germline Pathogenicity v2019

Classification was made for transcript:

Our verdict: Pathogenic. The variant received 18 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	PS1Same amino acid change as known pathogenic		Same AA change, ≥2-star ClinVar pathogenic — very strong (PS1); ClinVar contains 1 P/LP entry with the same amino acid change (highest review level: 2 stars).
	PM1Mutational hot spot or critical domain		Missense neighbourhood hotspot (≥2 P/LP within ±8 AA, OR ≥ 5 vs. background) — PM1; In-domain: 0 pathogenic, 0 benign rare missense variants.; ±8 AA neighbourhood: 8 pathogenic, 1 benign (OR vs. background: 28.3).
	PM2Absent/extremely low in population databases		Absent from gnomAD (AR/unknown gene) — PM2; Absent from gnomAD at well-covered site (MOI: AR) (base 0.001, raised to 0.0049 by highest known P/LP ClinVar AF 0.0049) — PM2 moderate.
	PM5Novel missense at known pathogenic residue		Different pathogenic missense at same AA residue in ClinVar (PM5); ClinVar contains a germline Pathogenic/Likely Pathogenic entry at the same amino acid position with a different amino acid change: p.C241R: Likely_pathogenic (ClinVar VariationId 2847057, 1 star)
	PP3Computational evidence supports damaging effect		Germline meta computational scorer (REVEL/MetaRNN/BayesDel) predicts damaging effect — strong evidence (PP3); Splicing verdict: not pathogenic.; Germline computational verdict: pathogenic (Strong).

Variant Effect in Transcripts

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

RefSeq Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	PMM2 NM_000303.3	MANE Select	c.721T>A p.Cys241Ser	missense	Exon 8 of 8	Prot: NP_000294.1 UniProt:

PMM2 NM_000303.3

MANE Select

HGVSc / HGVSpc.721T>Ap.Cys241Ser

Exon rankExon 8 of 8

missense

Prot: NP_000294.1UniProt: O15305-1A0A0S2Z4J6

Ensembl Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	PMM2 ENST00000268261.9	TSL:1MANE Select	c.721T>A p.Cys241Ser	missense	Exon 8 of 8	Prot: ENSP00000268261.4 UniProt:
	PMM2 ENST00000565221.5	TSL:1	n.*339T>A	3_prime_UTR	Exon 6 of 6	Prot: ENSP00000457932.1 UniProt:
	PMM2 ENST00000566540.5	TSL:1	n.*343T>A	3_prime_UTR	Exon 6 of 6	Prot: ENSP00000454284.1 UniProt:

PMM2 ENST00000268261.9

TSL:1MANE Select

HGVSc / HGVSpc.721T>Ap.Cys241Ser

Exon rankExon 8 of 8

missense

Prot: ENSP00000268261.4UniProt: O15305-1

PMM2 ENST00000565221.5

TSL:1

HGVSc / HGVSpn.*339T>A

Exon rankExon 6 of 6

3_prime_UTR

Prot: ENSP00000457932.1UniProt: H3BV34

PMM2 ENST00000566540.5

TSL:1

HGVSc / HGVSpn.*343T>A

Exon rankExon 6 of 6

3_prime_UTR

Prot: ENSP00000454284.1UniProt: H3BM92

Frequencies

Allele frequencies (AF), counts (AC/AN), homozygotes and coverage

Common (AF > 0.05 / Hom > 5)

Rare (AF ≤ 0.0001 / Hom ≤ 1)

Source / population	AF	AC	Hom	AN	Coverage
Global population databases 3 sources Large-scale international reference populations
GnomAD3 genomes	AF:	AC:	Hom:	AN:	Cov:33
GnomAD4 exome	AF:	AC:	Hom:	AN:	Cov:30
GnomAD4 genome	AF:	AC:	Hom:	AN:	Cov:33

Showing 3 sources

ClinVar

Not reported in ClinVar

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Pathogenic	25
AlphaMissense	Pathogenic	0.74
BayesDel_addAF	Pathogenic	0.52	D
BayesDel_noAF	Pathogenic	0.51
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.91	D
Eigen	Uncertain	0.65
Eigen_PC	Uncertain	0.56
FATHMM_MKL	Pathogenic	0.98	D
FuncVEP CTI	Pathogenic	0.87
GPN-Star LLR	N/A	-6.6
GPN-Star score	N/A	6.6
LIST_S2	Uncertain	0.93	D
M_CAP	Pathogenic	0.31	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.1	D
Mutation Taster	N/A	41/59	disease causing
MutationAssessor	Pathogenic	3.1	M
PhyloP100	Uncertain	5.0
popEVE	Benign	-3.0
PrimateAI	Uncertain	0.68	T
PROVEAN	Uncertain	-3.0	D
RBP_binding_hub_radar	N/A	0.0
RBP_regulation_power_radar	N/A	1.7
REVEL	Pathogenic	0.94
Sift	Benign	0.042	D
Sift4G	Benign	0.21	T
Varity_R	N/A	0.93
VESM-3B	Benign	-8.8

Showing 30 of 30 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
Pangolin (max)	Benign	0.010
SpliceAI score (max)	Benign	0.0	Details are displayed if max score is > 0.2

Showing 2 of 2 scores

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

MaveDB functional evidence

MaveDB is a public repository of laboratory assays that test the effect of thousands of variants at once — treat this as supporting research data and interpret it with great caution; it is not a clinical classification.

No MaveDB functional evidence found for this variant.

Other links and lift over

hg19: chr16-8941662;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar