rs730882051

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2PP3_StrongPP5

The ENST00000476832.2(ALG2):​c.203T>G​(p.Val68Gly) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V68M) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Consequence

ALG2
ENST00000476832.2 missense

Scores

10
7
2

Clinical Significance

Pathogenic no assertion criteria provided P:1

Conservation

PhyloP100: 5.04
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 Likely_pathogenic. Variant got 7 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.99
PP5
Variant 9-99221692-A-C is Pathogenic according to our data. Variant chr9-99221692-A-C is described in ClinVar as [Pathogenic]. Clinvar id is 183019.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
ALG2NM_033087.4 linkuse as main transcriptc.203T>G p.Val68Gly missense_variant 1/2 ENST00000476832.2 NP_149078.1
ALG2NR_024532.2 linkuse as main transcriptn.251T>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.203T>G p.Val68Gly missense_variant 1/21 NM_033087.4 ENSP00000417764 P1Q9H553-1
ALG2ENST00000238477.5 linkuse as main transcriptc.203T>G p.Val68Gly missense_variant, NMD_transcript_variant 1/32 ENSP00000432675

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
Cov.:
32
GnomAD4 genome
Cov.:
33

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:1
Revision: no assertion criteria provided
LINK: link

Submissions by phenotype

Congenital myasthenic syndrome 14 Pathogenic:1
Pathogenic, no assertion criteria providedliterature onlyOMIMMar 01, 2013- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.71
BayesDel_addAF
Pathogenic
0.44
D
BayesDel_noAF
Pathogenic
0.39
CADD
Pathogenic
26
DANN
Uncertain
0.99
DEOGEN2
Uncertain
0.65
D
Eigen
Uncertain
0.61
Eigen_PC
Uncertain
0.47
FATHMM_MKL
Uncertain
0.88
D
LIST_S2
Benign
0.64
T
M_CAP
Pathogenic
0.91
D
MetaRNN
Pathogenic
0.99
D
MetaSVM
Uncertain
0.75
D
MutationAssessor
Pathogenic
3.7
H
MutationTaster
Benign
1.0
D
PrimateAI
Uncertain
0.66
T
PROVEAN
Pathogenic
-6.3
D
REVEL
Pathogenic
0.88
Sift
Pathogenic
0.0
D
Sift4G
Pathogenic
0.0
D
Polyphen
1.0
D
Vest4
0.82
MutPred
0.85
Gain of disorder (P = 0.028);
MVP
0.94
MPC
0.85
ClinPred
0.99
D
GERP RS
4.7
Varity_R
0.96
gMVP
0.94

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

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

Other links and lift over

dbSNP: rs730882051; hg19: chr9-101983974; API