16-8811197-T-C

Variant names:

• chr16-8811197-T-C
• rs11074924
• NM_000303.3:c.447+19T>C

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.447+19T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.499 in 1,445,742 control chromosomes in the GnomAD database, including 184,852 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.43 (15301 hom., cov: 33)
  • Exomes 𝑓: 0.51 (169551 hom.)
• Consequence: PMM2 NM_000303.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: -1.15
• Publications: 15 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), Orphanet, PanelApp Australia, ClinGen

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 16-8811197-T-C is Benign according to our data. Variant chr16-8811197-T-C is described in ClinVar as Benign. ClinVar VariationId is 92802.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.52 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PMM2	NM_000303.3	MANE Select	c.447+19T>C		intron	N/A	NP_000294.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PMM2	ENST00000268261.9	TSL:1 MANE Select	c.447+19T>C		intron	N/A	ENSP00000268261.4
	PMM2	ENST00000565221.5	TSL:1	n.*65+19T>C		intron	N/A	ENSP00000457932.1
	PMM2	ENST00000566540.5	TSL:1	n.*70-441T>C		intron	N/A	ENSP00000454284.1

Frequencies

GnomAD3 genomes AF: 0.435 AC: 66100 AN: 151962 Hom.: 15303 Cov.: 33

Gnomad AFR AF: 0.270

Gnomad AMI AF: 0.441

Gnomad AMR AF: 0.368

Gnomad ASJ AF: 0.545

Gnomad EAS AF: 0.442

Gnomad SAS AF: 0.397

Gnomad FIN AF: 0.577

Gnomad MID AF: 0.418

Gnomad NFE AF: 0.525

Gnomad OTH AF: 0.433

GnomAD2 exomes AF: 0.464 AC: 76028 AN: 163720 AF XY: 0.466

Gnomad AFR exome AF: 0.261

Gnomad AMR exome AF: 0.364

Gnomad ASJ exome AF: 0.540

Gnomad EAS exome AF: 0.444

Gnomad FIN exome AF: 0.573

Gnomad NFE exome AF: 0.524

Gnomad OTH exome AF: 0.465

GnomAD4 exome AF: 0.507 AC: 655769 AN: 1293662 Hom.: 169551 Cov.: 19 AF XY: 0.504 AC XY: 324406 AN XY: 644096

African (AFR) AF: 0.264 AC: 7833 AN: 29634

American (AMR) AF: 0.367 AC: 13254 AN: 36130

Ashkenazi Jewish (ASJ) AF: 0.546 AC: 13513 AN: 24758

East Asian (EAS) AF: 0.463 AC: 16454 AN: 35554

South Asian (SAS) AF: 0.399 AC: 31035 AN: 77730

European-Finnish (FIN) AF: 0.575 AC: 28275 AN: 49158

Middle Eastern (MID) AF: 0.407 AC: 2242 AN: 5514

European-Non Finnish (NFE) AF: 0.527 AC: 516708 AN: 980654

Other (OTH) AF: 0.485 AC: 26455 AN: 54530

GnomAD4 genome AF: 0.435 AC: 66116 AN: 152080 Hom.: 15301 Cov.: 33 AF XY: 0.431 AC XY: 32072 AN XY: 74340

African (AFR) AF: 0.270 AC: 11196 AN: 41484

American (AMR) AF: 0.368 AC: 5621 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.545 AC: 1892 AN: 3472

East Asian (EAS) AF: 0.442 AC: 2285 AN: 5172

South Asian (SAS) AF: 0.398 AC: 1918 AN: 4824

European-Finnish (FIN) AF: 0.577 AC: 6088 AN: 10548

Middle Eastern (MID) AF: 0.415 AC: 122 AN: 294

European-Non Finnish (NFE) AF: 0.525 AC: 35679 AN: 67980

Other (OTH) AF: 0.433 AC: 914 AN: 2112

Alfa AF: 0.390 Hom.: 2406

Bravo AF: 0.414

Asia WGS AF: 0.414 AC: 1439 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	4	PMM2-congenital disorder of glycosylation (4)
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	0.054
DANN	Benign	0.40
PhyloP100		-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: rs11074924; hg19: chr16-8905054; COSMIC: COSV51630710; COSMIC: COSV51630710;