2-74462544-G-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_006302.3(MOGS):c.1245C>G(p.Ile415Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00284 in 1,610,242 control chromosomes in the GnomAD database, including 38 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. I415I) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0098 ( 22 hom., cov: 33)

Exomes 𝑓: 0.0021 ( 16 hom. )

Consequence

MOGS
NM_006302.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: -0.0140

Publications

4 publications found

Variant links:

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]

MOGS Gene-Disease associations (from GenCC):

MOGS-congenital disorder of glycosylation
Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Ambry Genetics, G2P, Orphanet, PanelApp Australia, ClinGen, Labcorp Genetics (formerly Invitae)

MOGS links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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

BP4

Computational evidence support a benign effect (MetaRNN=0.0016709566).

BP6

Variant 2-74462544-G-C is Benign according to our data. Variant chr2-74462544-G-C is described in ClinVar as Benign. ClinVar VariationId is 382459.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 = 0.00978 (1490/152316) while in subpopulation AFR AF = 0.0318 (1322/41568). AF 95% confidence interval is 0.0304. There are 22 homozygotes in GnomAd4. There are 696 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 22 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MOGS	NM_006302.3 link	c.1245C>G	p.Ile415Met	missense_variant	Exon 4 of 4	ENST00000448666.7	NP_006293.2
MOGS	NM_001146158.2 link	c.927C>G	p.Ile309Met	missense_variant	Exon 5 of 5		NP_001139630.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MOGS	ENST00000448666.7 link	c.1245C>G	p.Ile415Met	missense_variant	Exon 4 of 4	1	NM_006302.3	ENSP00000410992.3

Frequencies

GnomAD3 genomes

AF:

0.00973

AC:

1481

AN:

152198

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0317

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00327

Gnomad ASJ

AF:

0.00173

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00311

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.00123

Gnomad OTH

AF:

0.00574

GnomAD2 exomes

AF:

0.00342

AC:

849

AN:

247952

AF XY:

0.00304

show subpopulations

Gnomad AFR exome

AF:

0.0315

Gnomad AMR exome

AF:

0.00128

Gnomad ASJ exome

AF:

0.00336

Gnomad EAS exome

AF:

0.000111

Gnomad FIN exome

AF:

0.0000467

Gnomad NFE exome

AF:

0.000872

Gnomad OTH exome

AF:

0.00282

GnomAD4 exome

AF:

0.00211

AC:

3078

AN:

1457926

Hom.:

Cov.:

AF XY:

0.00210

AC XY:

1524

AN XY:

724700

show subpopulations

African (AFR)

AF:

0.0312

AC:

1040

AN:

33324

American (AMR)

AF:

0.00133

AC:

AN:

44474

Ashkenazi Jewish (ASJ)

AF:

0.00263

AC:

AN:

25904

East Asian (EAS)

AF:

0.000126

AC:

AN:

39614

South Asian (SAS)

AF:

0.00558

AC:

481

AN:

86124

European-Finnish (FIN)

AF:

0.000263

AC:

AN:

53248

Middle Eastern (MID)

AF:

0.00696

AC:

AN:

5748

European-Non Finnish (NFE)

AF:

0.00106

AC:

1181

AN:

1109320

Other (OTH)

AF:

0.00316

AC:

190

AN:

60170

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

Heterozygous variant carriers

218

437

655

874

1092

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

132

198

264

330

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00978

AC:

1490

AN:

152316

Hom.:

Cov.:

AF XY:

0.00935

AC XY:

696

AN XY:

74478

show subpopulations

African (AFR)

AF:

0.0318

AC:

1322

AN:

41568

American (AMR)

AF:

0.00327

AC:

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.00173

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5182

South Asian (SAS)

AF:

0.00290

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00123

AC:

AN:

68030

Other (OTH)

AF:

0.00568

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

138

206

275

344

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00151

Hom.:

Bravo

AF:

0.0109

TwinsUK

AF:

0.000809

AC:

ALSPAC

AF:

0.000778

AC:

ESP6500AA

AF:

0.0288

AC:

113

ESP6500EA

AF:

0.00145

AC:

ExAC

AF:

0.00397

AC:

480

Asia WGS

AF:

0.00462

AC:

AN:

3478

EpiCase

AF:

0.00115

EpiControl

AF:

0.000771

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:1

Apr 21, 2016

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

Jan 29, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

not provided

Benign:1

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

AlphaMissense

Benign

0.053

BayesDel_addAF

Benign

-0.60

BayesDel_noAF

Benign

-0.61

CADD

Benign

7.2

(source)

DANN

Benign

0.72

DEOGEN2

Benign

0.0036

T;T;.;.;.;.

Eigen

Benign

-0.97

Eigen_PC

Benign

-0.90

FATHMM_MKL

Benign

0.023

LIST_S2

Benign

0.0

.;T;.;T;T;T

MetaRNN

Benign

0.0017

T;T;T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.90

L;L;.;.;.;.

PhyloP100

-0.014

PrimateAI

Benign

0.29

PROVEAN

Benign

0.0

.;N;.;.;N;.

REVEL

Benign

0.020

Sift

Pathogenic

0.0

.;T;.;.;T;.

Sift4G

Pathogenic

0.0

.;T;.;.;T;.

Vest4

0.0

ClinPred

0.000024

GERP RS

1.7

Varity_R

0.050

gMVP

0.32

Mutation Taster

=100/0

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over