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

Genomes: 𝑓 0.00012 ( 0 hom., 6 hem., cov: 23)
Exomes 𝑓: 0.000039 ( 1 hom. 13 hem. )

Consequence

LAMP2
NM_013995.2 missense

Scores

13

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.200
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.04498282).
BS2
High Hemizygotes in GnomAd4 at 6 XL gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
LAMP2NM_002294.3 linkc.1093+2532G>A intron_variant Intron 8 of 8 ENST00000200639.9 NP_002285.1 P13473-1
LAMP2NM_013995.2 linkc.1189G>A p.Val397Ile missense_variant Exon 9 of 9 NP_054701.1 P13473-2
LAMP2NM_001122606.1 linkc.1093+2532G>A intron_variant Intron 8 of 8 NP_001116078.1 P13473-3

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
LAMP2ENST00000200639.9 linkc.1093+2532G>A intron_variant Intron 8 of 8 1 NM_002294.3 ENSP00000200639.4 P13473-1

Frequencies

GnomAD3 genomes
AF:
0.000116
AC:
13
AN:
111775
Hom.:
0
Cov.:
23
AF XY:
0.000177
AC XY:
6
AN XY:
33967
show subpopulations
Gnomad AFR
AF:
0.000228
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000113
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000109
AC:
2
AN:
183347
Hom.:
1
AF XY:
0.00
AC XY:
0
AN XY:
67861
show subpopulations
Gnomad AFR exome
AF:
0.000152
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000393
AC:
43
AN:
1094910
Hom.:
1
Cov.:
28
AF XY:
0.0000361
AC XY:
13
AN XY:
360396
show subpopulations
Gnomad4 AFR exome
AF:
0.0000759
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000477
Gnomad4 OTH exome
AF:
0.0000217
GnomAD4 genome
AF:
0.000116
AC:
13
AN:
111775
Hom.:
0
Cov.:
23
AF XY:
0.000177
AC XY:
6
AN XY:
33967
show subpopulations
Gnomad4 AFR
AF:
0.000228
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000113
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000142
Hom.:
1
Bravo
AF:
0.000178
ExAC
AF:
0.0000165
AC:
2

ClinVar

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

Submissions by phenotype

Danon disease Uncertain:1
Sep 22, 2016
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Benign
-0.60
T
BayesDel_noAF
Benign
-0.84
CADD
Benign
19
DANN
Benign
0.91
FATHMM_MKL
Benign
0.66
D
LIST_S2
Benign
0.067
T
M_CAP
Benign
0.0055
T
MetaRNN
Benign
0.045
T
MetaSVM
Benign
-1.0
T
PROVEAN
Benign
0.71
N
REVEL
Benign
0.031
Sift
Benign
0.24
T
Sift4G
Benign
0.27
T
Polyphen
0.0
B
Vest4
0.058
MVP
0.32
ClinPred
0.061
T
GERP RS
2.5
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

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: rs730880488; hg19: chrX-119573053; COSMIC: COSV52354939; API