rs184209905

chr2-74462908-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_006302.3(MOGS):c.881C>T(p.Pro294Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000578 in 1,613,892 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P294A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0029 (4 hom., cov: 33)
  • Exomes 𝑓: 0.00034 (3 hom.)
• Consequence: MOGS NM_006302.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 2.26

Genes affected

MOGS (HGNC:24862): (mannosyl-oligosaccharide glucosidase) This gene encodes the first enzyme in the N-linked oligosaccharide processing pathway. The enzyme cleaves the distal alpha-1,2-linked glucose residue from the Glc(3)-Man(9)-GlcNAc(2) oligosaccharide precursor. This protein is located in the lumen of the endoplasmic reticulum. Defects in this gene are a cause of type IIb congenital disorder of glycosylation (CDGIIb). Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Mar 2009]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0114937425).
• BP6: Variant 2-74462908-G-A is Benign according to our data. Variant chr2-74462908-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 235622.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0029 (442/152342) while in subpopulation AFR AF= 0.0101 (420/41594). AF 95% confidence interval is 0.0093. There are 4 homozygotes in gnomad4. There are 207 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MOGS	NM_006302.3	c.881C>T	p.Pro294Leu	missense_variant	4/4	ENST00000448666.7
MOGS	NM_001146158.2	c.563C>T	p.Pro188Leu	missense_variant	5/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MOGS	ENST00000448666.7	c.881C>T	p.Pro294Leu	missense_variant	4/4	1	NM_006302.3	P1

Frequencies

GnomAD3 genomes AF: 0.00290 AC: 442 AN: 152224 Hom.: 4 Cov.: 33

Gnomad AFR AF: 0.0101

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00124

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000675 AC: 168 AN: 249036 Hom.: 1 AF XY: 0.000488 AC XY: 66 AN XY: 135220

Gnomad AFR exome AF: 0.00983

Gnomad AMR exome AF: 0.000377

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000177

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000336 AC: 491 AN: 1461550 Hom.: 3 Cov.: 31 AF XY: 0.000281 AC XY: 204 AN XY: 727090

Gnomad4 AFR exome AF: 0.0122

Gnomad4 AMR exome AF: 0.000335

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000126

Gnomad4 OTH exome AF: 0.000828

GnomAD4 genome AF: 0.00290 AC: 442 AN: 152342 Hom.: 4 Cov.: 33 AF XY: 0.00278 AC XY: 207 AN XY: 74502

Gnomad4 AFR AF: 0.0101

Gnomad4 AMR AF: 0.00124

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000577 Hom.: 1

Bravo AF: 0.00364

ESP6500AA AF: 0.00742 AC: 29

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000877 AC: 106

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Dec 09, 2016

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

MOGS-congenital disorder of glycosylation Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 25, 2024

- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Aug 29, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.079
BayesDel_addAF	Benign	-0.49	T
BayesDel_noAF	Benign	-0.46
Cadd	Benign	23
Dann	Benign	0.91
DEOGEN2	Benign	0.0073	T;T;.;.;.;.
Eigen	Benign	-0.27
Eigen_PC	Benign	-0.12
FATHMM_MKL	Benign	0.63	D
MetaRNN	Benign	0.011	T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.61	N;N;.;.;.;.
MutationTaster	Benign	0.98	D;D;D;D
PrimateAI	Uncertain	0.52	T
REVEL	Benign	0.032
Polyphen		0.0030	B;B;.;.;.;.
Vest4		0.26, 0.28
MVP		0.46
MPC		0.28
ClinPred		0.011	T
GERP RS		4.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.068
gMVP		0.63

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

Publications

LitVar

Other links and lift over

dbSNP: rs184209905; hg19: chr2-74690035;