NM_000303.3:c.178+142C>A

Variant names:

• chr16-8802052-C-A
• rs2304471
• NM_000303.3:c.178+142C>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.00800
• Publications: 4 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 -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.

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.178+142C>A		intron	N/A	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.178+142C>A		intron	N/A	ENSP00000268261.4	O15305-1
	PMM2	ENST00000565221.5	TSL:1	n.178+142C>A		intron	N/A	ENSP00000457932.1	H3BV34
	PMM2	ENST00000566540.5	TSL:1	n.178+142C>A		intron	N/A	ENSP00000454284.1	H3BM92

Frequencies

GnomAD3 genomes AF: 0.193 AC: 29328 AN: 151958 Hom.: 3000 Cov.: 32

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

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.: 5 AF XY: 0.224 AC XY: 62068 AN XY: 276562

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

GnomAD4 genome AF: 0.193 AC: 29360 AN: 152076 Hom.: 3005 Cov.: 32 AF XY: 0.196 AC XY: 14601 AN XY: 74328

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: 55 AN: 294

European-Non Finnish (NFE) AF: 0.203 AC: 13773 AN: 67982

Other (OTH) AF: 0.194 AC: 409 AN: 2108

Alfa AF: 0.199 Hom.: 1916

Bravo AF: 0.187

Asia WGS AF: 0.309 AC: 1074 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	6.4
DANN	Benign	0.48
PhyloP100		-0.0080
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2304471; hg19: chr16-8895909;