7-141652792-A-AGG
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1_ModeratePM2PP5_Very_Strong
The NM_018238.4(AGK):c.1141_1142dupGG(p.Ser382AlafsTer17) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Consequence
NM_018238.4 frameshift
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 |
---|---|---|---|---|---|---|---|---|
AGK | NM_018238.4 | c.1141_1142dupGG | p.Ser382AlafsTer17 | frameshift_variant | Exon 16 of 16 | ENST00000649286.2 | NP_060708.1 | |
AGK | XM_011516397.4 | c.1141_1142dupGG | p.Ser382AlafsTer17 | frameshift_variant | Exon 16 of 16 | XP_011514699.1 | ||
AGK | XM_024446835.2 | c.1141_1142dupGG | p.Ser382AlafsTer17 | frameshift_variant | Exon 16 of 16 | XP_024302603.1 |
Ensembl
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome Cov.: 30
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
not provided Pathogenic:1
The c.1141_1142dupGG variant in the AGK gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. The c.1141_1142dupGG variant causes a frameshift starting with codon Serine 382, changes this amino acid to a Alanine residue, and creates a premature Stop codon at position 17 of the new reading frame, denoted p.Ser382AlafsX17. This variant is predicted to cause loss of normal protein function through protein truncation. The c.1141_1142dupGG variant is not observed in large population cohorts (Lek et al., 2016). We interpret c.1141_1142dupGG as a likely pathogenic variant. -
Sengers syndrome;C3553494:Cataract 38 Pathogenic:1
This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Ser382Alafs*17) in the AGK gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 41 amino acid(s) of the AGK protein. This premature translational stop signal has been observed in individual(s) with clinical features of Sengers syndrome (Invitae). ClinVar contains an entry for this variant (Variation ID: 524160). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. This variant disrupts a region of the AGK protein in which other variant(s) (p.Tyr390Serfs*9) have been determined to be pathogenic (Invitae). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at