rs141541387

chrX-120446414-A-CchrX-120446414-A-G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_ModerateBP6_Very_StrongBS2

The NM_002294.3(LAMP2):c.755T>G(p.Ile252Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00181 in 1,208,328 control chromosomes in the GnomAD database, including 2 homozygotes. There are 695 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I252T) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0012 ( 0 hom., 30 hem., cov: 22)

Exomes 𝑓: 0.0019 ( 2 hom. 665 hem. )

Consequence

LAMP2
NM_002294.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:15

Conservation

PhyloP100: 4.15

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 -14 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.09243721).

BP6

Variant X-120446414-A-C is Benign according to our data. Variant chrX-120446414-A-C is described in ClinVar as [Likely_benign]. Clinvar id is 44437.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-120446414-A-C is described in Lovd as [Benign]. Variant chrX-120446414-A-C is described in Lovd as [Likely_benign].

BS2

High Hemizygotes in GnomAd at 30 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
LAMP2	NM_002294.3 linkuse as main transcript	c.755T>G	p.Ile252Ser	missense_variant	6/9	ENST00000200639.9
LAMP2	NM_001122606.1 linkuse as main transcript	c.755T>G	p.Ile252Ser	missense_variant	6/9
LAMP2	NM_013995.2 linkuse as main transcript	c.755T>G	p.Ile252Ser	missense_variant	6/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LAMP2	ENST00000200639.9 linkuse as main transcript	c.755T>G	p.Ile252Ser	missense_variant	6/9	1	NM_002294.3	P3	P13473-1

Frequencies

GnomAD3 genomes

AF:

0.00117

AC:

130

AN:

111435

Hom.:

Cov.:

AF XY:

0.000893

AC XY:

AN XY:

33593

show subpopulations

Gnomad AFR

AF:

0.000360

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00115

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000167

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00196

Gnomad OTH

AF:

0.00133

GnomAD3 exomes

AF:

0.00105

AC:

193

AN:

183379

Hom.:

AF XY:

0.00114

AC XY:

AN XY:

67835

show subpopulations

Gnomad AFR exome

AF:

0.000228

Gnomad AMR exome

AF:

0.00102

Gnomad ASJ exome

AF:

0.000134

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000125

Gnomad NFE exome

AF:

0.00188

Gnomad OTH exome

AF:

0.00110

GnomAD4 exome

AF:

0.00188

AC:

2058

AN:

1096838

Hom.:

Cov.:

AF XY:

0.00184

AC XY:

665

AN XY:

362244

show subpopulations

Gnomad4 AFR exome

AF:

0.000341

Gnomad4 AMR exome

AF:

0.000994

Gnomad4 ASJ exome

AF:

0.000103

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000987

Gnomad4 NFE exome

AF:

0.00230

Gnomad4 OTH exome

AF:

0.00154

GnomAD4 genome

AF:

0.00117

AC:

130

AN:

111490

Hom.:

Cov.:

AF XY:

0.000891

AC XY:

AN XY:

33658

show subpopulations

Gnomad4 AFR

AF:

0.000359

Gnomad4 AMR

AF:

0.00114

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000167

Gnomad4 NFE

AF:

0.00196

Gnomad4 OTH

AF:

0.00131

Alfa

AF:

0.00209

Hom.:

Bravo

AF:

0.00127

TwinsUK

AF:

0.00135

AC:

ALSPAC

AF:

0.000692

AC:

ESP6500AA

AF:

0.000261

AC:

ESP6500EA

AF:

0.00253

AC:

ExAC

AF:

0.00107

AC:

130

EpiCase

AF:

0.00234

EpiControl

AF:

0.00237

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:15

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:7

Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 15, 2013	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	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 28, 2015	- -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 10, 2023	- -
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	Feb 24, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 14, 2022	The p.Ile252Ser variant in LAMP2 is classified as benign because it has been identified in 0.18% (169/92563) of European chromosomes, including 1 homozygote, by gnomAD (http://gnomad.broadinstitute.org). ACMG/AMP Criteria applied: BA1. -

Danon disease

Benign:4

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Apr 15, 2022	- -

not provided

Benign:2

Likely benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

Cardiomyopathy

Benign:1

Benign, criteria provided, single submitter

clinical testing

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Nov 17, 2022

- -

Cardiovascular phenotype

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

May 31, 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

AlphaMissense

Uncertain

0.46

BayesDel_addAF

Benign

-0.41

BayesDel_noAF

Benign

-0.36

Cadd

Pathogenic

Dann

Uncertain

0.99

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.88

D;D;D

M_CAP

Benign

0.052

MetaRNN

Benign

0.092

T;T;T

MetaSVM

Benign

-0.86

MutationAssessor

Uncertain

2.7

M;M;M

MutationTaster

Benign

0.80

N;N;N;N;N

PrimateAI

Uncertain

0.61

PROVEAN

Uncertain

-3.8

D;D;D

REVEL

Benign

0.17

Sift

Uncertain

0.0040

D;D;D

Sift4G

Uncertain

0.0090

D;D;D

Polyphen

0.65, 0.73

.;P;P

Vest4

0.59

MVP

0.76

MPC

0.52

ClinPred

0.051

GERP RS

4.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.75

gMVP

0.89

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