2-74461280-A-C

Variant names:

• chr2-74461280-A-C
• rs3191651
• NM_006302.3:c.2509T>G

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_006302.3(MOGS):​c.2509T>G​(p.Tyr837Asp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Y837H) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: MOGS NM_006302.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 8.27
• Publications: 2 publications found

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)

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.838

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MOGS	NM_006302.3	c.2509T>G	p.Tyr837Asp	missense_variant	Exon 4 of 4	ENST00000448666.7	NP_006293.2
MOGS	NM_001146158.2	c.2191T>G	p.Tyr731Asp	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	c.2509T>G	p.Tyr837Asp	missense_variant	Exon 4 of 4	1	NM_006302.3	ENSP00000410992.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.46
BayesDel_addAF	Pathogenic	0.28	D
BayesDel_noAF	Pathogenic	0.16
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Benign	0.077	T;T;.;.;.
Eigen	Pathogenic	0.71
Eigen_PC	Pathogenic	0.67
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.68	.;T;.;T;T
M_CAP	Uncertain	0.13	D
MetaRNN	Pathogenic	0.84	D;D;D;D;D
MetaSVM	Benign	-0.65	T
MutationAssessor	Uncertain	2.1	M;M;.;.;.
PhyloP100		8.3
PrimateAI	Uncertain	0.71	T
PROVEAN	Pathogenic	-9.3	.;D;.;.;D
REVEL	Pathogenic	0.68
Sift	Pathogenic	0.0	.;D;.;.;D
Sift4G	Pathogenic	0.0	.;D;.;.;D
Polyphen		1.0	D;D;.;.;.
Vest4		0.91, 0.91
MutPred		0.62		Loss of helix (P = 0.028);Loss of helix (P = 0.028);.;.;.;
MVP		0.72
MPC		1.2
ClinPred		1.0	D
GERP RS		4.8
Varity_R		0.92
gMVP		0.93
Mutation Taster		=46/54	disease causing

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: rs3191651; hg19: chr2-74688407;