14-49620826-C-T

Position:

• chr14-49620826-C-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_002408.4(MGAT2):​c.-443C>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00491 in 621,508 control chromosomes in the GnomAD database, including 27 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0059 (8 hom., cov: 34)
  • Exomes 𝑓: 0.0046 (19 hom.)
• Consequence: MGAT2 NM_002408.4 5_prime_UTR
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:1
• Conservation: PhyloP100: -0.539

Genes affected

MGAT2 (HGNC:7045): (alpha-1,6-mannosyl-glycoprotein 2-beta-N-acetylglucosaminyltransferase) The product of this gene is a Golgi enzyme catalyzing an essential step in the conversion of oligomannose to complex N-glycans. The enzyme has the typical glycosyltransferase domains: a short N-terminal cytoplasmic domain, a hydrophobic non-cleavable signal-anchor domain, and a C-terminal catalytic domain. Mutations in this gene may lead to carbohydrate-deficient glycoprotein syndrome, type II. The coding region of this gene is intronless. Transcript variants with a spliced 5' UTR may exist, but their biological validity has not been determined. [provided by RefSeq, Jul 2008]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.52).
• BP6: Variant 14-49620826-C-T is Benign according to our data. Variant chr14-49620826-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 313241.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=2}.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00589 (897/152304) while in subpopulation AFR AF= 0.00878 (365/41568). AF 95% confidence interval is 0.00804. There are 8 homozygotes in gnomad4. There are 518 alleles in male gnomad4 subpopulation. Median coverage is 34. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 8 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MGAT2	NM_002408.4	c.-443C>T		5_prime_UTR_variant	1/1	ENST00000305386.4	NP_002399.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MGAT2	ENST00000305386.4	c.-443C>T		5_prime_UTR_variant	1/1		NM_002408.4	ENSP00000307423	P1
	ENST00000555043.1	n.2458G>A		non_coding_transcript_exon_variant	2/2	2

Frequencies

GnomAD3 genomes AF: 0.00584 AC: 889 AN: 152186 Hom.: 7 Cov.: 34

Gnomad AFR AF: 0.00859

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00281

Gnomad ASJ AF: 0.00317

Gnomad EAS AF: 0.00135

Gnomad SAS AF: 0.00620

Gnomad FIN AF: 0.0276

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00197

Gnomad OTH AF: 0.00621

GnomAD4 exome AF: 0.00460 AC: 2156 AN: 469204 Hom.: 19 Cov.: 0 AF XY: 0.00463 AC XY: 1161 AN XY: 250814

Gnomad4 AFR exome AF: 0.00817

Gnomad4 AMR exome AF: 0.00392

Gnomad4 ASJ exome AF: 0.00235

Gnomad4 EAS exome AF: 0.000492

Gnomad4 SAS exome AF: 0.00749

Gnomad4 FIN exome AF: 0.0262

Gnomad4 NFE exome AF: 0.00203

Gnomad4 OTH exome AF: 0.00614

GnomAD4 genome AF: 0.00589 AC: 897 AN: 152304 Hom.: 8 Cov.: 34 AF XY: 0.00696 AC XY: 518 AN XY: 74476

Gnomad4 AFR AF: 0.00878

Gnomad4 AMR AF: 0.00281

Gnomad4 ASJ AF: 0.00317

Gnomad4 EAS AF: 0.00116

Gnomad4 SAS AF: 0.00621

Gnomad4 FIN AF: 0.0276

Gnomad4 NFE AF: 0.00197

Gnomad4 OTH AF: 0.00615

Alfa AF: 0.00401 Hom.: 0

Bravo AF: 0.00406

Asia WGS AF: 0.0140 AC: 49 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

MGAT2-congenital disorder of glycosylation Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Congenital disorder of glycosylation Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 06, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.52
CADD	Benign	3.6
DANN	Benign	0.89
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0

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: rs3007037; hg19: chr14-50087544;