Genetic Variant NM_033087.4:c.304C>G (chr9-99221591-G-C) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_033087.4(ALG2):c.304C>G(p.Leu102Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. L102L) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

ALG2
NM_033087.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.748

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:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.1247879).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ALG2	NM_033087.4 link	c.304C>G	p.Leu102Val	missense_variant	Exon 1 of 2	ENST00000476832.2	NP_149078.1	Q9H553-1A0A024R184
ALG2	NR_024532.2 link	n.352C>G		non_coding_transcript_exon_variant	Exon 1 of 3
ALG2	XM_047423996.1 link	c.-544C>G		upstream_gene_variant			XP_047279952.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ALG2	ENST00000476832.2 link	c.304C>G	p.Leu102Val	missense_variant	Exon 1 of 2	1	NM_033087.4	ENSP00000417764.1		Q9H553-1
ALG2	ENST00000238477.5 link	n.304C>G		non_coding_transcript_exon_variant	Exon 1 of 3	2		ENSP00000432675.2		A0A0A0MTE0

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1391752

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

686610

African (AFR)

AF:

0.00

AC:

AN:

31498

American (AMR)

AF:

0.00

AC:

AN:

35624

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25114

East Asian (EAS)

AF:

0.00

AC:

AN:

35674

South Asian (SAS)

AF:

0.00

AC:

AN:

79282

European-Finnish (FIN)

AF:

0.00

AC:

AN:

43236

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5658

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1077848

Other (OTH)

AF:

0.00

AC:

AN:

57818

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.091

BayesDel_addAF

Benign

-0.16

BayesDel_noAF

Benign

-0.46

CADD

Benign

(source)

DANN

Benign

0.86

DEOGEN2

Benign

0.15

Eigen

Benign

-0.41

Eigen_PC

Benign

-0.21

FATHMM_MKL

Benign

0.57

LIST_S2

Benign

0.70

M_CAP

Benign

0.012

MetaRNN

Benign

0.12

MetaSVM

Benign

-0.90

MutationAssessor

Benign

0.055

PhyloP100

0.75

PrimateAI

Uncertain

0.52

PROVEAN

Benign

0.77

REVEL

Benign

0.14

Sift

Benign

0.92

Sift4G

Benign

0.93

Polyphen

0.015

Vest4

0.16

MutPred

0.55

Gain of catalytic residue at L102 (P = 0.073);

MVP

0.57

MPC

0.19

ClinPred

0.13

GERP RS

4.0

PromoterAI

0.031

Neutral

(source)

Varity_R

0.20

gMVP

0.68

Mutation Taster

=91/9

polymorphism

(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

Computational scores

Splicing

Publications

Other links and lift over