ENST00000371335.4:c.1171G>A

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The ENST00000371335.4(LAMP2):​c.1171G>A​(p.Val391Ile) variant causes a missense change. The variant allele was found at a frequency of 0.00681 in 1,207,482 control chromosomes in the GnomAD database, including 24 homozygotes. There are 2,640 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 10/14 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0039 ( 0 hom., 111 hem., cov: 23)
Exomes 𝑓: 0.0071 ( 24 hom. 2529 hem. )

Consequence

LAMP2
ENST00000371335.4 missense

Scores

13

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:16

Conservation

PhyloP100: 5.91
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 -9 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.0050724447).
BP6
Variant X-120439216-C-T is Benign according to our data. Variant chrX-120439216-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 45573.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Benign=4, Likely_benign=3}. Variant chrX-120439216-C-T is described in Lovd as [Benign]. Variant chrX-120439216-C-T is described in Lovd as [Likely_benign].
BS2
High Hemizygotes in GnomAd4 at 111 XL gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
LAMP2NM_002294.3 linkc.1093+2514G>A intron_variant Intron 8 of 8 ENST00000200639.9 NP_002285.1 P13473-1
LAMP2NM_013995.2 linkc.1171G>A p.Val391Ile missense_variant Exon 9 of 9 NP_054701.1 P13473-2
LAMP2NM_001122606.1 linkc.1093+2514G>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+2514G>A intron_variant Intron 8 of 8 1 NM_002294.3 ENSP00000200639.4 P13473-1

Frequencies

GnomAD3 genomes
AF:
0.00394
AC:
440
AN:
111597
Hom.:
0
Cov.:
23
AF XY:
0.00328
AC XY:
111
AN XY:
33833
show subpopulations
Gnomad AFR
AF:
0.000814
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00105
Gnomad ASJ
AF:
0.00151
Gnomad EAS
AF:
0.000834
Gnomad SAS
AF:
0.00186
Gnomad FIN
AF:
0.00235
Gnomad MID
AF:
0.00418
Gnomad NFE
AF:
0.00696
Gnomad OTH
AF:
0.00465
GnomAD3 exomes
AF:
0.00387
AC:
709
AN:
183335
Hom.:
0
AF XY:
0.00458
AC XY:
311
AN XY:
67847
show subpopulations
Gnomad AFR exome
AF:
0.000684
Gnomad AMR exome
AF:
0.000766
Gnomad ASJ exome
AF:
0.000668
Gnomad EAS exome
AF:
0.000289
Gnomad SAS exome
AF:
0.00372
Gnomad FIN exome
AF:
0.00137
Gnomad NFE exome
AF:
0.00685
Gnomad OTH exome
AF:
0.00376
GnomAD4 exome
AF:
0.00711
AC:
7787
AN:
1095836
Hom.:
24
Cov.:
28
AF XY:
0.00700
AC XY:
2529
AN XY:
361326
show subpopulations
Gnomad4 AFR exome
AF:
0.000455
Gnomad4 AMR exome
AF:
0.000909
Gnomad4 ASJ exome
AF:
0.00108
Gnomad4 EAS exome
AF:
0.0000663
Gnomad4 SAS exome
AF:
0.00412
Gnomad4 FIN exome
AF:
0.00210
Gnomad4 NFE exome
AF:
0.00845
Gnomad4 OTH exome
AF:
0.00678
GnomAD4 genome
AF:
0.00394
AC:
440
AN:
111646
Hom.:
0
Cov.:
23
AF XY:
0.00328
AC XY:
111
AN XY:
33892
show subpopulations
Gnomad4 AFR
AF:
0.000812
Gnomad4 AMR
AF:
0.00105
Gnomad4 ASJ
AF:
0.00151
Gnomad4 EAS
AF:
0.000837
Gnomad4 SAS
AF:
0.00187
Gnomad4 FIN
AF:
0.00235
Gnomad4 NFE
AF:
0.00696
Gnomad4 OTH
AF:
0.00460
Alfa
AF:
0.00601
Hom.:
240
Bravo
AF:
0.00356
TwinsUK
AF:
0.0108
AC:
40
ALSPAC
AF:
0.00900
AC:
26
ESP6500AA
AF:
0.000782
AC:
3
ESP6500EA
AF:
0.00654
AC:
44
ExAC
AF:
0.00426
AC:
517
EpiCase
AF:
0.00758
EpiControl
AF:
0.00818

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:1Benign:16
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not specified Benign:7
Dec 14, 2015
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

p.Val391Ile in exon 9B of LAMP2: This variant is not expected to have clinical s ignificance because it has been identified in 0.6% (294/47993) of European chrom osomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org ; dbSNP rs144140265). -

Mar 28, 2011
Stanford Center for Inherited Cardiovascular Disease, Stanford University
Significance: Benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease -

-
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
Significance: Benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Apr 30, 2012
GeneDx
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Jul 21, 2016
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

-
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+
Significance: Benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

-
Clinical Genetics, Academic Medical Center
Significance: Benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

not provided Uncertain:1Benign:3
-
Genome Diagnostics Laboratory, University Medical Center Utrecht
Significance: Likely benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Aug 16, 2017
Mayo Clinic Laboratories, Mayo Clinic
Significance: Benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Sep 20, 2016
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Jun 01, 2016
CeGaT Center for Human Genetics Tuebingen
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Danon disease Benign:3
-
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Significance: Likely benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Dec 16, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Oct 06, 2023
Molecular Genetics, Royal Melbourne Hospital
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

LAMP2-related disorder Benign:1
May 20, 2019
PreventionGenetics, part of Exact Sciences
Significance: Benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Hypertrophic cardiomyopathy Benign:1
Sep 29, 2022
Cohesion Phenomics
Significance: Likely benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Cardiovascular phenotype Benign:1
Oct 13, 2017
Ambry Genetics
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Benign
-0.66
T
BayesDel_noAF
Benign
-0.70
CADD
Benign
20
DANN
Benign
0.54
FATHMM_MKL
Benign
0.74
D
LIST_S2
Benign
0.66
T
M_CAP
Benign
0.0031
T
MetaRNN
Benign
0.0051
T
MetaSVM
Benign
-0.98
T
PROVEAN
Benign
0.43
N
REVEL
Benign
0.085
Sift
Benign
1.0
T
Sift4G
Benign
1.0
T
Polyphen
0.0030
B
Vest4
0.077
MVP
0.44
ClinPred
0.019
T
GERP RS
3.5
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: rs144140265; hg19: chrX-119573071; API