rs34258285

Variant names:

• chr16-8813057-A-C
• rs34258285
• NM_000303.3:c.590A>C

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 3P and 20B. PM1 PP2 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000303.3(PMM2):​c.590A>C​(p.Glu197Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.023 in 1,613,114 control chromosomes in the GnomAD database, including 535 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E197V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.020 (58 hom., cov: 33)
  • Exomes 𝑓: 0.023 (477 hom.)
• Consequence: PMM2 NM_000303.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:15
• Conservation: PhyloP100: 2.25
• Publications: 22 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: Benign. The variant received -17 ACMG points.

• PM1: In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 14 uncertain in NM_000303.3
• 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, hyperinsulinemic hypoglycemia with polycystic kidney disease.
• BP4: Computational evidence support a benign effect (MetaRNN=0.0045259).
• BP6: Variant 16-8813057-A-C is Benign according to our data. Variant chr16-8813057-A-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 92803.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0201 (3067/152354) while in subpopulation NFE AF = 0.0281 (1909/68028). AF 95% confidence interval is 0.027. There are 58 homozygotes in GnomAd4. There are 1505 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 58 AR gene

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.590A>C	p.Glu197Ala	missense	Exon 7 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.590A>C	p.Glu197Ala	missense	Exon 7 of 8	ENSP00000268261.4	O15305-1
	PMM2	ENST00000565221.5	TSL:1	n.*208A>C		non_coding_transcript_exon	Exon 5 of 6	ENSP00000457932.1	H3BV34
	PMM2	ENST00000566540.5	TSL:1	n.*212A>C		non_coding_transcript_exon	Exon 5 of 6	ENSP00000454284.1	H3BM92

Frequencies

GnomAD3 genomes AF: 0.0201 AC: 3067 AN: 152236 Hom.: 58 Cov.: 33

Gnomad AFR AF: 0.00408

Gnomad AMI AF: 0.0515

Gnomad AMR AF: 0.0209

Gnomad ASJ AF: 0.0101

Gnomad EAS AF: 0.000770

Gnomad SAS AF: 0.00393

Gnomad FIN AF: 0.0490

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0281

Gnomad OTH AF: 0.0210

GnomAD2 exomes AF: 0.0200 AC: 5018 AN: 251472 AF XY: 0.0200

Gnomad AFR exome AF: 0.00320

Gnomad AMR exome AF: 0.0132

Gnomad ASJ exome AF: 0.0117

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0506

Gnomad NFE exome AF: 0.0265

Gnomad OTH exome AF: 0.0220

GnomAD4 exome AF: 0.0233 AC: 33972 AN: 1460760 Hom.: 477 Cov.: 30 AF XY: 0.0230 AC XY: 16723 AN XY: 726750

African (AFR) AF: 0.00362 AC: 121 AN: 33468

American (AMR) AF: 0.0151 AC: 677 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.0117 AC: 305 AN: 26124

East Asian (EAS) AF: 0.00 AC: 0 AN: 39692

South Asian (SAS) AF: 0.00521 AC: 449 AN: 86244

European-Finnish (FIN) AF: 0.0507 AC: 2710 AN: 53416

Middle Eastern (MID) AF: 0.00625 AC: 36 AN: 5764

European-Non Finnish (NFE) AF: 0.0257 AC: 28520 AN: 1110960

Other (OTH) AF: 0.0191 AC: 1154 AN: 60370

GnomAD4 genome AF: 0.0201 AC: 3067 AN: 152354 Hom.: 58 Cov.: 33 AF XY: 0.0202 AC XY: 1505 AN XY: 74502

African (AFR) AF: 0.00406 AC: 169 AN: 41584

American (AMR) AF: 0.0208 AC: 319 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.0101 AC: 35 AN: 3472

East Asian (EAS) AF: 0.000772 AC: 4 AN: 5184

South Asian (SAS) AF: 0.00393 AC: 19 AN: 4832

European-Finnish (FIN) AF: 0.0490 AC: 520 AN: 10622

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0281 AC: 1909 AN: 68028

Other (OTH) AF: 0.0208 AC: 44 AN: 2116

Alfa AF: 0.0238 Hom.: 148

Bravo AF: 0.0173

TwinsUK AF: 0.0227 AC: 84

ALSPAC AF: 0.0270 AC: 104

ESP6500AA AF: 0.00478 AC: 21

ESP6500EA AF: 0.0255 AC: 219

ExAC AF: 0.0193 AC: 2343

Asia WGS AF: 0.00375 AC: 13 AN: 3478

EpiCase AF: 0.0259

EpiControl AF: 0.0258

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	7	not specified (7)
-	-	6	PMM2-congenital disorder of glycosylation (6)
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Uncertain	0.020
CADD	Benign	21
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.78	D
Eigen	Benign	-0.30
Eigen_PC	Benign	-0.19
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Benign	0.74	T
MetaRNN	Benign	0.0045	T
MetaSVM	Uncertain	0.36	D
MutationAssessor	Benign	1.8	L
PhyloP100		2.2
PrimateAI	Uncertain	0.49	T
PROVEAN	Uncertain	-3.2	D
REVEL	Uncertain	0.58
Sift	Benign	0.079	T
Sift4G	Benign	0.096	T
Polyphen		0.0020	B
Vest4		0.085
MPC		0.0080
ClinPred		0.021	T
GERP RS		4.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.43
gMVP		0.79
Mutation Taster		=57/43	polymorphism (auto)

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

Other links and lift over

dbSNP: rs34258285; hg19: chr16-8906914; COSMIC: COSV99076565; COSMIC: COSV99076565;