rs766491800
Variant summary
Our verdict is Likely benign. Variant got -1 ACMG points: 0P and 1B. BP4
The NM_002294.3(LAMP2):c.443A>G(p.Asn148Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000116 in 1,202,195 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 4 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Genomes: 𝑓 0.000053 ( 0 hom., 1 hem., cov: 23)
Exomes 𝑓: 0.0000073 ( 0 hom. 3 hem. )
Consequence
LAMP2
NM_002294.3 missense
NM_002294.3 missense
Scores
1
4
12
Clinical Significance
Conservation
PhyloP100: 2.19
Genes affected
LAMP2 (HGNC:6501): (lysosomal associated membrane protein 2) The protein encoded by this gene is a member of a family of membrane glycoproteins. This glycoprotein provides selectins with carbohydrate ligands. It may play a role in tumor cell metastasis. It may also function in the protection, maintenance, and adhesion of the lysosome. Alternative splicing of this gene results in multiple transcript variants encoding distinct proteins. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Likely_benign. Variant got -1 ACMG points.
BP4
?
Computational evidence support a benign effect (MetaRNN=0.31337184).
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
LAMP2 | NM_002294.3 | c.443A>G | p.Asn148Ser | missense_variant | 4/9 | ENST00000200639.9 | |
LAMP2 | NM_001122606.1 | c.443A>G | p.Asn148Ser | missense_variant | 4/9 | ||
LAMP2 | NM_013995.2 | c.443A>G | p.Asn148Ser | missense_variant | 4/9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
LAMP2 | ENST00000200639.9 | c.443A>G | p.Asn148Ser | missense_variant | 4/9 | 1 | NM_002294.3 | P3 |
Frequencies
GnomAD3 genomes ? AF: 0.0000533 AC: 6AN: 112554Hom.: 0 Cov.: 23 AF XY: 0.0000288 AC XY: 1AN XY: 34686
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GnomAD3 exomes AF: 0.0000164 AC: 3AN: 182411Hom.: 0 AF XY: 0.0000149 AC XY: 1AN XY: 66985
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GnomAD4 exome AF: 0.00000734 AC: 8AN: 1089641Hom.: 0 Cov.: 28 AF XY: 0.00000845 AC XY: 3AN XY: 355229
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GnomAD4 genome ? AF: 0.0000533 AC: 6AN: 112554Hom.: 0 Cov.: 23 AF XY: 0.0000288 AC XY: 1AN XY: 34686
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Danon disease Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Aug 11, 2021 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Aug 29, 2022 | This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 148 of the LAMP2 protein (p.Asn148Ser). This variant is present in population databases (rs766491800, gnomAD 0.004%), including at least one homozygous and/or hemizygous individual. This variant has not been reported in the literature in individuals affected with LAMP2-related conditions. ClinVar contains an entry for this variant (Variation ID: 578311). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Jul 11, 2019 | Has not been previously published as pathogenic or benign to our knowledge; In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect - |
Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Jul 12, 2023 | The p.N148S variant (also known as c.443A>G), located in coding exon 4 of the LAMP2 gene, results from an A to G substitution at nucleotide position 443. The asparagine at codon 148 is replaced by serine, an amino acid with highly similar properties. Based on data from gnomAD, the G allele has an overall frequency of 0.0016% (3/182411) total alleles studied, with 1 hemizygote(s) observed. The highest observed frequency was 0.0037% (3/81412) of European (non-Finnish) alleles. This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
CardioboostCm
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
Cadd
Benign
Dann
Uncertain
FATHMM_MKL
Benign
N
LIST_S2
Benign
T;T;T
M_CAP
Benign
D
MetaRNN
Benign
T;T;T
MetaSVM
Benign
T
MutationAssessor
Pathogenic
M;M;M
MutationTaster
Benign
N;N;N;N;N
PrimateAI
Benign
T
PROVEAN
Uncertain
D;D;D
REVEL
Benign
Sift
Uncertain
D;D;D
Sift4G
Uncertain
D;D;D
Polyphen
0.93, 0.92
.;P;P
Vest4
MutPred
Loss of stability (P = 0.0641);Loss of stability (P = 0.0641);Loss of stability (P = 0.0641);
MVP
MPC
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
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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