2-74464937-T-C

Variant names:

• chr2-74464937-T-C
• ENST00000452063.7:c.-8A>G

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_001146158.2(MOGS):​c.-8A>G variant causes a 5 prime UTR premature start codon gain change. The variant allele was found at a frequency of 0.00000069 in 1,449,770 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: MOGS NM_001146158.2 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.25

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 Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.969

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MOGS	NM_006302.3	c.311A>G	p.Tyr104Cys	missense_variant	Exon 1 of 4	ENST00000448666.7	NP_006293.2
MOGS	NM_001146158.2	c.-8A>G		5_prime_UTR_premature_start_codon_gain_variant	Exon 2 of 5		NP_001139630.1
MOGS	NM_001146158.2	c.-8A>G		5_prime_UTR_variant	Exon 2 of 5		NP_001139630.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MOGS	ENST00000448666.7	c.311A>G	p.Tyr104Cys	missense_variant	Exon 1 of 4	1	NM_006302.3	ENSP00000410992.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.90e-7 AC: 1 AN: 1449770 Hom.: 0 Cov.: 31 AF XY: 0.00000139 AC XY: 1 AN XY: 719662

Gnomad4 AFR exome AF: 0.0000300

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.76
BayesDel_addAF	Pathogenic	0.35	D
BayesDel_noAF	Pathogenic	0.26
CADD	Pathogenic	29
DANN	Uncertain	0.99
DEOGEN2	Benign	0.15	T;T;T;.;.
Eigen	Uncertain	0.47
Eigen_PC	Uncertain	0.36
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Uncertain	0.93	.;D;D;D;D
M_CAP	Uncertain	0.25	D
MetaRNN	Pathogenic	0.97	D;D;D;D;D
MetaSVM	Uncertain	-0.10	T
MutationAssessor	Pathogenic	3.5	H;H;.;.;.
PrimateAI	Pathogenic	0.86	D
PROVEAN	Pathogenic	-8.3	.;D;D;.;.
REVEL	Uncertain	0.62
Sift	Uncertain	0.0010	.;D;D;.;.
Sift4G	Pathogenic	0.0	.;D;D;.;.
Polyphen		1.0	D;D;.;.;.
Vest4		0.86, 0.92
MutPred		0.89		Loss of phosphorylation at Y104 (P = 0.0149);Loss of phosphorylation at Y104 (P = 0.0149);Loss of phosphorylation at Y104 (P = 0.0149);Loss of phosphorylation at Y104 (P = 0.0149);Loss of phosphorylation at Y104 (P = 0.0149);
MVP		0.85
MPC		0.97
ClinPred		1.0	D
GERP RS		3.6
Varity_R		0.98
gMVP		0.98

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr2-74692064;