rs2072688

Variant names:

• chr16-8848000-G-A
• rs2072688
• NM_000303.3:c.*175G>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.*175G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.269 in 614,406 control chromosomes in the GnomAD database, including 22,908 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.26 (5473 hom., cov: 32)
  • Exomes 𝑓: 0.27 (17435 hom.)
• Consequence: PMM2 NM_000303.3 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.685
• Publications: 8 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

ENSG00000260350 (HGNC:58482):

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 16-8848000-G-A is Benign according to our data. Variant chr16-8848000-G-A is described in ClinVar as Benign. ClinVar VariationId is 321231.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.324 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.*175G>A		3_prime_UTR	Exon 8 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.*175G>A		3_prime_UTR	Exon 8 of 8	ENSP00000268261.4	O15305-1
	PMM2	ENST00000565221.5	TSL:1	n.*534G>A		non_coding_transcript_exon	Exon 6 of 6	ENSP00000457932.1	H3BV34
	PMM2	ENST00000566540.5	TSL:1	n.*538G>A		non_coding_transcript_exon	Exon 6 of 6	ENSP00000454284.1	H3BM92

Frequencies

GnomAD3 genomes AF: 0.265 AC: 40239 AN: 151944 Hom.: 5469 Cov.: 32

Gnomad AFR AF: 0.264

Gnomad AMI AF: 0.241

Gnomad AMR AF: 0.218

Gnomad ASJ AF: 0.222

Gnomad EAS AF: 0.320

Gnomad SAS AF: 0.338

Gnomad FIN AF: 0.298

Gnomad MID AF: 0.180

Gnomad NFE AF: 0.265

Gnomad OTH AF: 0.248

GnomAD4 exome AF: 0.270 AC: 124833 AN: 462346 Hom.: 17435 Cov.: 4 AF XY: 0.274 AC XY: 67065 AN XY: 244962

African (AFR) AF: 0.266 AC: 3538 AN: 13318

American (AMR) AF: 0.184 AC: 4448 AN: 24180

Ashkenazi Jewish (ASJ) AF: 0.216 AC: 3137 AN: 14510

East Asian (EAS) AF: 0.310 AC: 9518 AN: 30710

South Asian (SAS) AF: 0.333 AC: 16260 AN: 48870

European-Finnish (FIN) AF: 0.284 AC: 8289 AN: 29218

Middle Eastern (MID) AF: 0.231 AC: 468 AN: 2026

European-Non Finnish (NFE) AF: 0.264 AC: 72227 AN: 273082

Other (OTH) AF: 0.263 AC: 6948 AN: 26432

GnomAD4 genome AF: 0.265 AC: 40263 AN: 152060 Hom.: 5473 Cov.: 32 AF XY: 0.268 AC XY: 19891 AN XY: 74340

African (AFR) AF: 0.264 AC: 10927 AN: 41464

American (AMR) AF: 0.217 AC: 3323 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.222 AC: 770 AN: 3468

East Asian (EAS) AF: 0.320 AC: 1653 AN: 5172

South Asian (SAS) AF: 0.338 AC: 1627 AN: 4814

European-Finnish (FIN) AF: 0.298 AC: 3145 AN: 10566

Middle Eastern (MID) AF: 0.187 AC: 55 AN: 294

European-Non Finnish (NFE) AF: 0.265 AC: 18016 AN: 67974

Other (OTH) AF: 0.250 AC: 528 AN: 2112

Alfa AF: 0.255 Hom.: 6555

Bravo AF: 0.254

Asia WGS AF: 0.332 AC: 1155 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	2.3
DANN	Benign	0.68
PhyloP100		-0.69
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	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: rs2072688; hg19: chr16-8941857;