rs963221673

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_033087.4(ALG2):c.1177A>G(p.Arg393Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000131 in 152,244 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 33)

Consequence

ALG2
NM_033087.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.01

Publications

0 publications found

Variant links:

Genes affected

ALG2 (HGNC:23159): (ALG2 alpha-1,3/1,6-mannosyltransferase) This gene encodes a member of the glycosyltransferase 1 family. The encoded protein acts as an alpha 1,3 mannosyltransferase, mannosylating Man(2)GlcNAc(2)-dolichol diphosphate and Man(1)GlcNAc(2)-dolichol diphosphate to form Man(3)GlcNAc(2)-dolichol diphosphate. Defects in this gene have been associated with congenital disorder of glycosylation type Ih (CDG-Ii). Alternative splicing results in multiple transcript variants. [provided by RefSeq, Nov 2008]

ALG2 Gene-Disease associations (from GenCC):

congenital myasthenic syndrome 14
Inheritance: AR Classification: STRONG, MODERATE Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
ALG2-congenital disorder of glycosylation
Inheritance: Unknown, AR Classification: STRONG, MODERATE, SUPPORTIVE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, G2P, PanelApp Australia, Orphanet, Ambry Genetics
congenital myasthenic syndromes with glycosylation defect
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ALG2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.912

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ALG2	NM_033087.4 link	c.1177A>G	p.Arg393Gly	missense_variant	Exon 2 of 2	ENST00000476832.2	NP_149078.1	Q9H553-1A0A024R184
ALG2	XM_047423996.1 link	c.898A>G	p.Arg300Gly	missense_variant	Exon 2 of 2		XP_047279952.1
ALG2	NR_024532.2 link	n.1384A>G		non_coding_transcript_exon_variant	Exon 3 of 3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
ALG2	ENST00000476832.2 link	c.1177A>G	p.Arg393Gly	missense_variant	Exon 2 of 2	1	NM_033087.4	ENSP00000417764.1	Q9H553-1
ALG2	ENST00000319033.7 link	c.898A>G	p.Arg300Gly	missense_variant	Exon 2 of 2	1		ENSP00000326609.6	Q9H553-2
ALG2	ENST00000238477.5 link	n.*919A>G		non_coding_transcript_exon_variant	Exon 3 of 3	2		ENSP00000432675.2	A0A0A0MTE0
ALG2	ENST00000238477.5 link	n.*919A>G		3_prime_UTR_variant	Exon 3 of 3	2		ENSP00000432675.2	A0A0A0MTE0

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152244

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000482

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

Cov.:

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152244

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74384

show subpopulations

African (AFR)

AF:

0.0000482

AC:

AN:

41460

American (AMR)

AF:

0.00

AC:

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5202

South Asian (SAS)

AF:

0.00

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68038

Other (OTH)

AF:

0.00

AC:

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

ALG2-congenital disorder of glycosylation;C4015597:Congenital myasthenic syndrome 14

Uncertain:1

Feb 08, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C15"). ClinVar contains an entry for this variant (Variation ID: 566269). This variant has not been reported in the literature in individuals affected with ALG2-related conditions. This variant is present in population databases (no rsID available, gnomAD 0.01%). This sequence change replaces arginine, which is basic and polar, with glycine, which is neutral and non-polar, at codon 393 of the ALG2 protein (p.Arg393Gly). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.59

BayesDel_addAF

Pathogenic

0.31

BayesDel_noAF

Pathogenic

0.21

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.68

D;.

Eigen

Pathogenic

0.69

Eigen_PC

Uncertain

0.57

FATHMM_MKL

Uncertain

0.89

LIST_S2

Uncertain

0.93

D;D

M_CAP

Pathogenic

0.59

MetaRNN

Pathogenic

0.91

D;D

MetaSVM

Uncertain

0.54

MutationAssessor

Pathogenic

3.9

H;.

PhyloP100

3.0

PrimateAI

Benign

0.46

PROVEAN

Pathogenic

-5.3

D;D

REVEL

Pathogenic

0.87

Sift

Uncertain

0.013

D;D

Sift4G

Uncertain

0.013

D;D

Polyphen

1.0

D;D

Vest4

0.87

MutPred

0.67

Loss of MoRF binding (P = 0.023);.;

MVP

0.93

MPC

0.84

ClinPred

0.99

GERP RS

3.5

Varity_R

0.91

gMVP

0.87

Mutation Taster

=43/57

disease causing

(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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over