rs755705607

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1PM2PP3

The ENST00000476832.2(ALG2):ā€‹c.219C>Gā€‹(p.Asp73Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000213 in 1,409,948 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 (ā˜…). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D73H) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)
Exomes š‘“: 0.0000021 ( 0 hom. )

Consequence

ALG2
ENST00000476832.2 missense

Scores

3
13
3

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.10
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]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 5 ACMG points.

PM1
In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain in ENST00000476832.2
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.754

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
ALG2NM_033087.4 linkuse as main transcriptc.219C>G p.Asp73Glu missense_variant 1/2 ENST00000476832.2 NP_149078.1
ALG2NR_024532.2 linkuse as main transcriptn.267C>G non_coding_transcript_exon_variant 1/3

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
ALG2ENST00000476832.2 linkuse as main transcriptc.219C>G p.Asp73Glu missense_variant 1/21 NM_033087.4 ENSP00000417764 P1Q9H553-1
ALG2ENST00000238477.5 linkuse as main transcriptc.219C>G p.Asp73Glu missense_variant, NMD_transcript_variant 1/32 ENSP00000432675

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD3 exomes
AF:
0.00000614
AC:
1
AN:
162994
Hom.:
0
AF XY:
0.0000111
AC XY:
1
AN XY:
90340
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000150
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000213
AC:
3
AN:
1409948
Hom.:
0
Cov.:
32
AF XY:
0.00000430
AC XY:
3
AN XY:
698130
show subpopulations
Gnomad4 AFR exome
AF:
0.00
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:
0.00000183
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32
Bravo
AF:
0.00000378
ExAC
AF:
0.00000878
AC:
1

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
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpAug 30, 2016This sequence change replaces aspartic acid with glutamic acid at codon 73 of the ALG2 protein (p.Asp73Glu). The aspartic acid residue is highly conserved and there is a small physicochemical difference between aspartic acid and glutamic acid. This variant is present in population databases (rs755705607, ExAC 0.02%) but has not been reported in the literature in individuals with a ALG2-related disease. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). In summary, this variant is a rare missense change with uncertain impact on protein function. There is no indication that it causes disease, but the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
0.43
BayesDel_addAF
Uncertain
0.052
T
BayesDel_noAF
Benign
-0.16
CADD
Uncertain
25
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.53
D
Eigen
Uncertain
0.60
Eigen_PC
Uncertain
0.52
FATHMM_MKL
Uncertain
0.85
D
LIST_S2
Uncertain
0.91
D
M_CAP
Pathogenic
0.46
D
MetaRNN
Pathogenic
0.75
D
MetaSVM
Uncertain
0.17
D
MutationAssessor
Pathogenic
2.9
M
MutationTaster
Benign
1.0
D
PrimateAI
Uncertain
0.68
T
PROVEAN
Uncertain
-2.8
D
REVEL
Uncertain
0.53
Sift
Benign
0.032
D
Sift4G
Uncertain
0.018
D
Polyphen
1.0
D
Vest4
0.52
MutPred
0.62
Gain of MoRF binding (P = 0.1598);
MVP
0.81
MPC
0.57
ClinPred
0.99
D
GERP RS
4.7
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.71
gMVP
0.61

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs755705607; hg19: chr9-101983958; API