2-74462544-G-C

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.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. 14/20 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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.0140

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=0.0016709566).
• BP6: Variant 2-74462544-G-C is Benign according to our data. Variant chr2-74462544-G-C is described in ClinVar as [Benign]. Clinvar id 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 male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 22 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MOGS	NM_006302.3	c.1245C>G	p.Ile415Met	missense_variant	4/4	ENST00000448666.7
MOGS	NM_001146158.2	c.927C>G	p.Ile309Met	missense_variant	5/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MOGS	ENST00000448666.7	c.1245C>G	p.Ile415Met	missense_variant	4/4	1	NM_006302.3	P1

Frequencies

GnomAD3 genomes AF: 0.00973 AC: 1481 AN: 152198 Hom.: 22 Cov.: 33

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

GnomAD3 exomes AF: 0.00342 AC: 849 AN: 247952 Hom.: 7 AF XY: 0.00304 AC XY: 409 AN XY: 134608

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 SAS exome AF: 0.00545

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.: 16 Cov.: 31 AF XY: 0.00210 AC XY: 1524 AN XY: 724700

Gnomad4 AFR exome AF: 0.0312

Gnomad4 AMR exome AF: 0.00133

Gnomad4 ASJ exome AF: 0.00263

Gnomad4 EAS exome AF: 0.000126

Gnomad4 SAS exome AF: 0.00558

Gnomad4 FIN exome AF: 0.000263

Gnomad4 NFE exome AF: 0.00106

Gnomad4 OTH exome AF: 0.00316

GnomAD4 genome AF: 0.00978 AC: 1490 AN: 152316 Hom.: 22 Cov.: 33 AF XY: 0.00935 AC XY: 696 AN XY: 74478

Gnomad4 AFR AF: 0.0318

Gnomad4 AMR AF: 0.00327

Gnomad4 ASJ AF: 0.00173

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00290

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00123

Gnomad4 OTH AF: 0.00568

Alfa AF: 0.00151 Hom.: 3

Bravo AF: 0.0109

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.0288 AC: 113

ESP6500EA AF: 0.00145 AC: 12

ExAC AF: 0.00397 AC: 480

Asia WGS AF: 0.00462 AC: 16 AN: 3478

EpiCase AF: 0.00115

EpiControl AF: 0.000771

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Apr 21, 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 22, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.053
BayesDel_addAF	Benign	-0.60	T
BayesDel_noAF	Benign	-0.61
Cadd	Benign	7.2
Dann	Benign	0.72
DEOGEN2	Benign	0.0036	T;T;.;.;.;.
Eigen	Benign	-0.97
Eigen_PC	Benign	-0.90
FATHMM_MKL	Benign	0.023	N
MetaRNN	Benign	0.0017	T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.90	L;L;.;.;.;.
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.29	T
REVEL	Benign	0.020
Polyphen		0.0	B;B;.;.;.;.
Vest4		0.070, 0.080
MVP		0.34
MPC		0.24
ClinPred		0.000024	T
GERP RS		1.7
Varity_R		0.050
gMVP		0.32

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: rs34838944; hg19: chr2-74689671;