9-99221803-C-A

Variant summary

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

The NM_033087.4(ALG2):​c.92G>T​(p.Arg31Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000125 in 1,597,732 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. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R31P) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)
Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

ALG2
NM_033087.4 missense

Scores

12
6
1

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 6.87

Publications

2 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

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, 0.938

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
ALG2NM_033087.4 linkc.92G>T p.Arg31Leu missense_variant Exon 1 of 2 ENST00000476832.2 NP_149078.1 Q9H553-1A0A024R184
ALG2NR_024532.2 linkn.140G>T non_coding_transcript_exon_variant Exon 1 of 3

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
ALG2ENST00000476832.2 linkc.92G>T p.Arg31Leu missense_variant Exon 1 of 2 1 NM_033087.4 ENSP00000417764.1 Q9H553-1
ALG2ENST00000238477.5 linkn.92G>T non_coding_transcript_exon_variant Exon 1 of 3 2 ENSP00000432675.2 A0A0A0MTE0

Frequencies

GnomAD3 genomes
AF:
0.00000657
AC:
1
AN:
152220
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.000192
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
AF:
6.92e-7
AC:
1
AN:
1445512
Hom.:
0
Cov.:
32
AF XY:
0.00
AC XY:
0
AN XY:
719538
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
33420
American (AMR)
AF:
0.0000224
AC:
1
AN:
44638
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
26042
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39664
South Asian (SAS)
AF:
0.00
AC:
0
AN:
86140
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
38484
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5660
European-Non Finnish (NFE)
AF:
0.00
AC:
0
AN:
1111264
Other (OTH)
AF:
0.00
AC:
0
AN:
60200
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.425
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
GnomAD4 genome
AF:
0.00000657
AC:
1
AN:
152220
Hom.:
0
Cov.:
33
AF XY:
0.00
AC XY:
0
AN XY:
74368
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
41454
American (AMR)
AF:
0.00
AC:
0
AN:
15290
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3472
East Asian (EAS)
AF:
0.000192
AC:
1
AN:
5196
South Asian (SAS)
AF:
0.00
AC:
0
AN:
4836
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
10626
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
316
European-Non Finnish (NFE)
AF:
0.00
AC:
0
AN:
68024
Other (OTH)
AF:
0.00
AC:
0
AN:
2094
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.525
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
Alfa
AF:
0.00
Hom.:
0
Bravo
AF:
0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.83
BayesDel_addAF
Pathogenic
0.43
D
BayesDel_noAF
Pathogenic
0.38
CADD
Pathogenic
29
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.58
D
Eigen
Pathogenic
0.87
Eigen_PC
Pathogenic
0.74
FATHMM_MKL
Uncertain
0.95
D
LIST_S2
Pathogenic
0.98
D
M_CAP
Pathogenic
0.71
D
MetaRNN
Pathogenic
0.94
D
MetaSVM
Uncertain
0.74
D
MutationAssessor
Pathogenic
3.8
H
PhyloP100
6.9
PrimateAI
Uncertain
0.73
T
PROVEAN
Pathogenic
-6.2
D
REVEL
Pathogenic
0.84
Sift
Pathogenic
0.0
D
Sift4G
Uncertain
0.0020
D
Polyphen
1.0
D
Vest4
0.89
MutPred
0.71
Gain of loop (P = 0.1069);
MVP
0.87
MPC
0.83
ClinPred
1.0
D
GERP RS
4.7
PromoterAI
-0.00020
Neutral
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.97
gMVP
0.90
Mutation Taster
=5/95
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

Publications

Other links and lift over

dbSNP: rs1279623882; hg19: chr9-101984085; API