rs104894858

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

Genomes: not found (cov: 22)

Consequence

LAMP2
NM_002294.3 missense, splice_region

Scores

3
6
9
Splicing: ADA: 1.000
2

Clinical Significance

Pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 4.51
Variant links:
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 Uncertain_significance. Variant got 5 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.77
PP5
Variant X-120442599-C-A is Pathogenic according to our data. Variant chrX-120442599-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 835011.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
LAMP2NM_002294.3 linkc.928G>T p.Val310Phe missense_variant, splice_region_variant Exon 7 of 9 ENST00000200639.9 NP_002285.1 P13473-1
LAMP2NM_001122606.1 linkc.928G>T p.Val310Phe missense_variant, splice_region_variant Exon 7 of 9 NP_001116078.1 P13473-3
LAMP2NM_013995.2 linkc.928G>T p.Val310Phe missense_variant, splice_region_variant Exon 7 of 9 NP_054701.1 P13473-2

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
LAMP2ENST00000200639.9 linkc.928G>T p.Val310Phe missense_variant, splice_region_variant Exon 7 of 9 1 NM_002294.3 ENSP00000200639.4 P13473-1

Frequencies

GnomAD3 genomes
Cov.:
22
GnomAD4 exome
Cov.:
28
GnomAD4 genome
Cov.:
22

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Danon disease Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpAug 03, 2023This 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: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.11
CardioboostCm
Uncertain
0.17
BayesDel_addAF
Benign
-0.13
T
BayesDel_noAF
Benign
-0.43
CADD
Pathogenic
27
DANN
Uncertain
1.0
DEOGEN2
Benign
0.33
.;T;.
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Uncertain
0.90
D;D;D
M_CAP
Pathogenic
0.40
D
MetaRNN
Pathogenic
0.77
D;D;D
MetaSVM
Benign
-0.60
T
MutationAssessor
Uncertain
2.6
M;M;M
PrimateAI
Benign
0.46
T
PROVEAN
Uncertain
-2.5
N;N;N
REVEL
Uncertain
0.30
Sift
Benign
0.043
D;D;D
Sift4G
Benign
0.13
T;T;T
Polyphen
0.027, 0.98
.;B;D
Vest4
0.44
MutPred
0.74
Gain of sheet (P = 0.0827);Gain of sheet (P = 0.0827);Gain of sheet (P = 0.0827);
MVP
0.62
MPC
0.45
ClinPred
0.92
D
GERP RS
5.2
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.68
gMVP
0.43

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
1.0
dbscSNV1_RF
Pathogenic
1.0
SpliceAI score (max)
0.88
Details are displayed if max score is > 0.2
DS_DL_spliceai
0.88
Position offset: 0

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs104894858; hg19: chrX-119576454; API