chrX-120439198-C-T
Variant summary
Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2
The NM_013995.2(LAMP2):c.1189G>A(p.Val397Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000464 in 1,206,685 control chromosomes in the GnomAD database, including 1 homozygotes. There are 19 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 11/14 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V397L) has been classified as Uncertain significance.
Frequency
Consequence
NM_013995.2 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -8 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
LAMP2 | NM_002294.3 | c.1093+2532G>A | intron_variant | Intron 8 of 8 | ENST00000200639.9 | NP_002285.1 | ||
LAMP2 | NM_013995.2 | c.1189G>A | p.Val397Ile | missense_variant | Exon 9 of 9 | NP_054701.1 | ||
LAMP2 | NM_001122606.1 | c.1093+2532G>A | intron_variant | Intron 8 of 8 | NP_001116078.1 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.000116 AC: 13AN: 111775Hom.: 0 Cov.: 23 AF XY: 0.000177 AC XY: 6AN XY: 33967
GnomAD3 exomes AF: 0.0000109 AC: 2AN: 183347Hom.: 1 AF XY: 0.00 AC XY: 0AN XY: 67861
GnomAD4 exome AF: 0.0000393 AC: 43AN: 1094910Hom.: 1 Cov.: 28 AF XY: 0.0000361 AC XY: 13AN XY: 360396
GnomAD4 genome AF: 0.000116 AC: 13AN: 111775Hom.: 0 Cov.: 23 AF XY: 0.000177 AC XY: 6AN XY: 33967
ClinVar
Submissions by phenotype
Danon disease Uncertain:1
In summary, this variant is a rare missense change that is not predicted to affect protein function. There is no indication that it causes disease, but the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance. General algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD), suggest that this missense change is likely to be tolerated. However, these predictions have not been confirmed by published functional studies. This variant is present in population databases (rs730880488, ExAC 0.02%) but has not been reported in the literature in individuals with a LAMP2-related disease. This sequence change replaces valine with isoleucine at codon 397 of the LAMP2 protein (p.Val397Ile). The valine residue is weakly conserved and there is a small physicochemical difference between valine and isoleucine. The LAMP2 gene has multiple clinically relevant isoforms. The p.Val397Ile variant occurs in alternate transcript NM_013995.2, which corresponds to position c.1093+2532G>A in NM_002294.2 , the primary transcript listed in the Methods. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at