chrX-120442599-C-A
Variant summary
Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2PP3PP5_Moderate
The NM_002294.3(LAMP2):c.928G>T(p.Val310Phe) variant causes a missense, splice region change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★).
Frequency
Consequence
NM_002294.3 missense, splice_region
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Uncertain_significance. Variant got 5 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
LAMP2 | NM_002294.3 | c.928G>T | p.Val310Phe | missense_variant, splice_region_variant | Exon 7 of 9 | ENST00000200639.9 | NP_002285.1 | |
LAMP2 | NM_001122606.1 | c.928G>T | p.Val310Phe | missense_variant, splice_region_variant | Exon 7 of 9 | NP_001116078.1 | ||
LAMP2 | NM_013995.2 | c.928G>T | p.Val310Phe | missense_variant, splice_region_variant | Exon 7 of 9 | NP_054701.1 |
Ensembl
Frequencies
GnomAD3 genomes Cov.: 22
GnomAD4 exome Cov.: 28
GnomAD4 genome Cov.: 22
ClinVar
Submissions by phenotype
Danon disease Pathogenic:1
This sequence change replaces valine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 310 of the LAMP2 protein (p.Val310Phe). RNA analysis indicates that this missense change induces altered splicing and may result in an absent or disrupted protein product. For these reasons, this variant has been classified as Pathogenic. This variant disrupts the c.928G nucleotide in the LAMP2 gene. Other variant(s) that disrupt this nucleotide have been determined to be pathogenic (PMID: 15673802, 16217705, 19373884, 29753918). This suggests that this nucleotide is clinically significant, and that variants that disrupt this position are likely to be disease-causing. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this missense change results in skipping of exon 7 and introduces a premature termination codon (PMID: 33226119). The resulting mRNA is expected to undergo nonsense-mediated decay. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 835011). This missense change has been observed in individual(s) with Danon disease (PMID: 33226119). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at