Genetic Variant PMM2:c.178+142C>A (chr16-8802052-C-A) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000303.3(PMM2):c.178+142C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.211 in 659,834 control chromosomes in the GnomAD database, including 16,012 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.19 ( 3005 hom., cov: 32)

Exomes 𝑓: 0.22 ( 13007 hom. )

Consequence

PMM2
NM_000303.3 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -0.00800

Publications

4 publications found

Variant links:

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), Orphanet, PanelApp Australia, ClinGen

PMM2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.82).

BP6

Variant 16-8802052-C-A is Benign according to our data. Variant chr16-8802052-C-A is described in ClinVar as Benign. ClinVar VariationId is 1234913.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.314 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PMM2	NM_000303.3 link	c.178+142C>A		intron_variant	Intron 2 of 7	ENST00000268261.9	NP_000294.1	O15305-1A0A0S2Z4J6Q59F02
PMM2	XM_047434215.1 link	c.6+142C>A		intron_variant	Intron 1 of 5		XP_047290171.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PMM2	ENST00000268261.9 link	c.178+142C>A		intron_variant	Intron 2 of 7	1	NM_000303.3	ENSP00000268261.4		O15305-1

Frequencies

GnomAD3 genomes

AF:

0.193

AC:

29328

AN:

151958

Hom.:

3000

Cov.:

show subpopulations

Gnomad AFR

AF:

0.161

Gnomad AMI

AF:

0.115

Gnomad AMR

AF:

0.179

Gnomad ASJ

AF:

0.187

Gnomad EAS

AF:

0.326

Gnomad SAS

AF:

0.328

Gnomad FIN

AF:

0.161

Gnomad MID

AF:

0.184

Gnomad NFE

AF:

0.203

Gnomad OTH

AF:

0.191

GnomAD2 exomes

AF:

0.219

AC:

31247

AN:

142842

AF XY:

0.228

show subpopulations

Gnomad AFR exome

AF:

0.157

Gnomad AMR exome

AF:

0.155

Gnomad ASJ exome

AF:

0.190

Gnomad EAS exome

AF:

0.316

Gnomad FIN exome

AF:

0.166

Gnomad NFE exome

AF:

0.206

Gnomad OTH exome

AF:

0.204

GnomAD4 exome

AF:

0.217

AC:

110162

AN:

507758

Hom.:

13007

Cov.:

AF XY:

0.224

AC XY:

62068

AN XY:

276562

show subpopulations

African (AFR)

AF:

0.163

AC:

2346

AN:

14398

American (AMR)

AF:

0.155

AC:

5078

AN:

32740

Ashkenazi Jewish (ASJ)

AF:

0.189

AC:

3400

AN:

17972

East Asian (EAS)

AF:

0.317

AC:

8690

AN:

27442

South Asian (SAS)

AF:

0.323

AC:

19878

AN:

61570

European-Finnish (FIN)

AF:

0.162

AC:

5640

AN:

34834

Middle Eastern (MID)

AF:

0.206

AC:

773

AN:

3760

European-Non Finnish (NFE)

AF:

0.204

AC:

58725

AN:

288212

Other (OTH)

AF:

0.210

AC:

5632

AN:

26830

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

5252

10504

15757

21009

26261

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

440

880

1320

1760

2200

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.193

AC:

29360

AN:

152076

Hom.:

3005

Cov.:

AF XY:

0.196

AC XY:

14601

AN XY:

74328

show subpopulations

African (AFR)

AF:

0.161

AC:

6675

AN:

41502

American (AMR)

AF:

0.179

AC:

2726

AN:

15270

Ashkenazi Jewish (ASJ)

AF:

0.187

AC:

648

AN:

3470

East Asian (EAS)

AF:

0.327

AC:

1689

AN:

5172

South Asian (SAS)

AF:

0.328

AC:

1576

AN:

4812

European-Finnish (FIN)

AF:

0.161

AC:

1704

AN:

10556

Middle Eastern (MID)

AF:

0.187

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.203

AC:

13773

AN:

67982

Other (OTH)

AF:

0.194

AC:

409

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

1198

2396

3593

4791

5989

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

322

644

966

1288

1610

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.199

Hom.:

1916

Bravo

AF:

0.187

Asia WGS

AF:

0.309

AC:

1074

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Aug 17, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.82

CADD

Benign

6.4

(source)

DANN

Benign

0.48

PhyloP100

-0.0080

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over