rs2075827

Variant names:

• chr16-8847961-A-C
• rs2075827
• ENST00000565221.5:n.*495A>C

Your query was ambiguous. Multiple possible variants found:

• chr16-8847961-A-C
• chr16-8847961-A-T

Variant summary

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

The ENST00000565221.5(PMM2):​n.*495A>C variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.265 in 668,580 control chromosomes in the GnomAD database, including 24,247 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.25 (4994 hom., cov: 33)
  • Exomes 𝑓: 0.27 (19253 hom.)
• Consequence: PMM2 ENST00000565221.5 non_coding_transcript_exon
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.0670
• Publications: 14 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

ENSG00000260350 (HGNC:58482):

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 16-8847961-A-C is Benign according to our data. Variant chr16-8847961-A-C is described in ClinVar as Benign. ClinVar VariationId is 321229.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.326 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PMM2	NM_000303.3	c.*136A>C		3_prime_UTR_variant	Exon 8 of 8	ENST00000268261.9	NP_000294.1
PMM2	XM_047434215.1	c.*136A>C		3_prime_UTR_variant	Exon 6 of 6		XP_047290171.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PMM2	ENST00000268261.9	c.*136A>C		3_prime_UTR_variant	Exon 8 of 8	1	NM_000303.3	ENSP00000268261.4

Frequencies

GnomAD3 genomes AF: 0.253 AC: 38450 AN: 152032 Hom.: 4994 Cov.: 33

Gnomad AFR AF: 0.221

Gnomad AMI AF: 0.245

Gnomad AMR AF: 0.214

Gnomad ASJ AF: 0.223

Gnomad EAS AF: 0.321

Gnomad SAS AF: 0.340

Gnomad FIN AF: 0.298

Gnomad MID AF: 0.177

Gnomad NFE AF: 0.265

Gnomad OTH AF: 0.245

GnomAD4 exome AF: 0.268 AC: 138660 AN: 516430 Hom.: 19253 Cov.: 6 AF XY: 0.273 AC XY: 75198 AN XY: 275032

African (AFR) AF: 0.222 AC: 3327 AN: 14984

American (AMR) AF: 0.185 AC: 5683 AN: 30770

Ashkenazi Jewish (ASJ) AF: 0.220 AC: 3723 AN: 16924

East Asian (EAS) AF: 0.310 AC: 9735 AN: 31406

South Asian (SAS) AF: 0.337 AC: 18986 AN: 56282

European-Finnish (FIN) AF: 0.284 AC: 9162 AN: 32264

Middle Eastern (MID) AF: 0.237 AC: 541 AN: 2282

European-Non Finnish (NFE) AF: 0.264 AC: 80050 AN: 302828

Other (OTH) AF: 0.260 AC: 7453 AN: 28690

GnomAD4 genome AF: 0.253 AC: 38456 AN: 152150 Hom.: 4994 Cov.: 33 AF XY: 0.256 AC XY: 19070 AN XY: 74392

African (AFR) AF: 0.220 AC: 9135 AN: 41508

American (AMR) AF: 0.214 AC: 3269 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.223 AC: 774 AN: 3468

East Asian (EAS) AF: 0.320 AC: 1658 AN: 5174

South Asian (SAS) AF: 0.340 AC: 1639 AN: 4822

European-Finnish (FIN) AF: 0.298 AC: 3163 AN: 10598

Middle Eastern (MID) AF: 0.184 AC: 54 AN: 294

European-Non Finnish (NFE) AF: 0.265 AC: 18018 AN: 67976

Other (OTH) AF: 0.247 AC: 523 AN: 2116

Alfa AF: 0.258 Hom.: 21613

Bravo AF: 0.240

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

PMM2-congenital disorder of glycosylation Benign:2

Jul 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided Benign:2

Jun 29, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	1.4
DANN	Benign	0.53
PhyloP100		-0.067
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: rs2075827; hg19: chr16-8941818;