22-49910602-C-T
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM2PP3_ModeratePP5_Very_Strong
The NM_024105.4(ALG12):c.301G>A(p.Gly101Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000136 in 1,614,022 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 Likely pathogenic (★★).
Frequency
Consequence
NM_024105.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 12 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
ALG12 | NM_024105.4 | c.301G>A | p.Gly101Arg | missense_variant | Exon 4 of 10 | ENST00000330817.11 | NP_077010.1 | |
ALG12 | XM_017028936.2 | c.301G>A | p.Gly101Arg | missense_variant | Exon 4 of 10 | XP_016884425.1 | ||
ALG12 | XM_017028937.2 | c.301G>A | p.Gly101Arg | missense_variant | Exon 4 of 11 | XP_016884426.1 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000197 AC: 3AN: 152246Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.00000796 AC: 2AN: 251386Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135898
GnomAD4 exome AF: 0.0000130 AC: 19AN: 1461776Hom.: 0 Cov.: 32 AF XY: 0.00000963 AC XY: 7AN XY: 727180
GnomAD4 genome AF: 0.0000197 AC: 3AN: 152246Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1AN XY: 74380
ClinVar
Submissions by phenotype
ALG12-congenital disorder of glycosylation Pathogenic:2
Variant summary: ALG12 c.301G>A (p.Gly101Arg) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 251386 control chromosomes. c.301G>A has been reported in the literature in homozygous and compound heterozygous individuals affected with ALG12-Congenital Disorder Of Glycosylation (e.g. Kranz_2007, Lecca_2011). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 17506107, 21029365). ClinVar contains an entry for this variant (Variation ID: 3436). Based on the evidence outlined above, the variant was classified as likely pathogenic. -
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not provided Pathogenic:1
Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 31481313, 20638314, 21029365, 26805780, 17506107) -
ALG12-related disorder Pathogenic:1
The ALG12 c.301G>A variant is predicted to result in the amino acid substitution p.Gly101Arg. This variant was reported in the compound heterozygous state in individuals with congenital disorder of glycosylation 1g (Kranz et al. 2007. PubMed ID: 17506107; Kane et al. 2016. PubMed ID: 26805780). This variant is reported in 0.0018% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/22-50304250-C-T). This variant is interpreted as likely pathogenic. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at