rs387906281
Variant summary
Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PVS1_StrongPM2PP5_Moderate
The NM_033087.4(ALG2):c.1040del(p.Gly347ValfsTer27) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000552 in 1,611,228 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★).
Frequency
Genomes: 𝑓 0.000072 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000053 ( 0 hom. )
Consequence
ALG2
NM_033087.4 frameshift
NM_033087.4 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 7.50
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 8 ACMG points.
PVS1
?
Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.169 CDS is truncated, and there are 1 pathogenic variants in the truncated region.
PM2
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant 9-99218144-AC-A is Pathogenic according to our data. Variant chr9-99218144-AC-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2699.Status of the report is criteria_provided_single_submitter, 1 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ALG2 | NM_033087.4 | c.1040del | p.Gly347ValfsTer27 | frameshift_variant | 2/2 | ENST00000476832.2 | |
ALG2 | XM_047423996.1 | c.761del | p.Gly254ValfsTer27 | frameshift_variant | 2/2 | ||
ALG2 | NR_024532.2 | n.1247del | non_coding_transcript_exon_variant | 3/3 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ALG2 | ENST00000476832.2 | c.1040del | p.Gly347ValfsTer27 | frameshift_variant | 2/2 | 1 | NM_033087.4 | P1 | |
ALG2 | ENST00000319033.7 | c.761del | p.Gly254ValfsTer27 | frameshift_variant | 2/2 | 1 | |||
ALG2 | ENST00000238477.5 | c.*782del | 3_prime_UTR_variant, NMD_transcript_variant | 3/3 | 2 |
Frequencies
GnomAD3 genomes ? AF: 0.0000723 AC: 11AN: 152196Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.0000439 AC: 11AN: 250348Hom.: 0 AF XY: 0.0000444 AC XY: 6AN XY: 135286
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GnomAD4 exome AF: 0.0000535 AC: 78AN: 1459032Hom.: 0 Cov.: 31 AF XY: 0.0000483 AC XY: 35AN XY: 725338
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GnomAD4 genome ? AF: 0.0000723 AC: 11AN: 152196Hom.: 0 Cov.: 33 AF XY: 0.0000403 AC XY: 3AN XY: 74376
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ClinVar
Significance: Likely pathogenic
Submissions summary: Pathogenic:2
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Congenital disorder of glycosylation type II Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Jun 20, 2003 | - - |
ALG2-congenital disorder of glycosylation;C4015597:Congenital myasthenic syndrome 14 Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jun 20, 2022 | ClinVar contains an entry for this variant (Variation ID: 2699). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Experimental studies have shown that this premature translational stop signal affects ALG2 function (PMID: 12684507). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. This premature translational stop signal has been observed in individuals with ALG2-related disease (PMID: 12684507; Invitae). This variant is present in population databases (rs387906281, gnomAD 0.01%). This sequence change creates a premature translational stop signal (p.Gly347Valfs*27) in the ALG2 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 70 amino acid(s) of the ALG2 protein. - |
Computational scores
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at