rs144140265

chrX-120439216-C-T

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. 9/13 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

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]

LAMP2 links:

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: {Likely_benign=3, Benign=5, Uncertain_significance=1}. 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 GnomAd at 111 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
LAMP2	NM_002294.3 linkuse as main transcript	c.1093+2514G>A		intron_variant		ENST00000200639.9
LAMP2	NM_013995.2 linkuse as main transcript	c.1171G>A	p.Val391Ile	missense_variant	9/9
LAMP2	NM_001122606.1 linkuse as main transcript	c.1093+2514G>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LAMP2	ENST00000200639.9 linkuse as main transcript	c.1093+2514G>A		intron_variant		1	NM_002294.3	P3	P13473-1

Frequencies

GnomAD3 genomes

AF:

0.00394

AC:

440

AN:

111597

Hom.:

Cov.:

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.:

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.:

Cov.:

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.:

Cov.:

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:

ALSPAC

AF:

0.00900

AC:

ESP6500AA

AF:

0.000782

AC:

ESP6500EA

AF:

0.00654

AC:

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

Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	Jul 21, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Dec 14, 2015	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). -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 30, 2012	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. -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Stanford Center for Inherited Cardiovascular Disease, Stanford University	Mar 28, 2011	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 -

not provided

Uncertain:1Benign:3

Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Aug 16, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2016	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Sep 20, 2016	- -

Danon disease

Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Molecular Genetics, Royal Melbourne Hospital	Oct 06, 2023	- -
Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 22, 2024	- -

LAMP2-related condition

Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

May 20, 2019

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

Likely benign, no assertion criteria provided

clinical testing

Cohesion Phenomics

Sep 29, 2022

- -

Cardiovascular phenotype

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 13, 2017

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

BayesDel_noAF

Benign

-0.70

Cadd

Benign

Dann

Benign

0.54

FATHMM_MKL

Benign

0.74

LIST_S2

Benign

0.66

M_CAP

Benign

0.0031

MetaRNN

Benign

0.0051

MetaSVM

Benign

-0.98

MutationTaster

Benign

1.0

D;D;D;N;N

PROVEAN

Benign

0.43

REVEL

Benign

0.085

Sift

Benign

1.0

Sift4G

Benign

1.0

Polyphen

0.0030

Vest4

0.077

MVP

0.44

ClinPred

0.019

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over