rs138991195

Positions:

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 2P and 7B. PM1BP4_ModerateBP6BS2

The NM_002294.3(LAMP2):c.586A>T(p.Thr196Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000399 in 1,208,560 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 160 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00041 ( 0 hom., 13 hem., cov: 23)

Exomes 𝑓: 0.00040 ( 0 hom. 147 hem. )

Consequence

LAMP2
NM_002294.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:13

Conservation

PhyloP100: 1.45

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 Likely_benign. Variant got -5 ACMG points.

PM1

In a glycosylation_site O-linked (GalNAc...) threonine (size 0) in uniprot entity LAMP2_HUMAN

BP4

Computational evidence support a benign effect (MetaRNN=0.07970959).

BP6

Variant X-120447996-T-A is Benign according to our data. Variant chrX-120447996-T-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 44432.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=7, Benign=1, Uncertain_significance=1}. Variant chrX-120447996-T-A is described in Lovd as [Likely_benign].

BS2

High Hemizygotes in GnomAd4 at 13 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
LAMP2	NM_002294.3 linkuse as main transcript	c.586A>T	p.Thr196Ser	missense_variant	5/9	ENST00000200639.9	NP_002285.1
LAMP2	NM_001122606.1 linkuse as main transcript	c.586A>T	p.Thr196Ser	missense_variant	5/9		NP_001116078.1
LAMP2	NM_013995.2 linkuse as main transcript	c.586A>T	p.Thr196Ser	missense_variant	5/9		NP_054701.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LAMP2	ENST00000200639.9 linkuse as main transcript	c.586A>T	p.Thr196Ser	missense_variant	5/9	1	NM_002294.3	ENSP00000200639	P3	P13473-1

Frequencies

GnomAD3 genomes

AF:

0.000414

AC:

AN:

111131

Hom.:

Cov.:

AF XY:

0.000390

AC XY:

AN XY:

33341

show subpopulations

Gnomad AFR

AF:

0.000131

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000288

Gnomad ASJ

AF:

0.00114

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000679

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000332

AC:

AN:

183475

Hom.:

AF XY:

0.000471

AC XY:

AN XY:

67915

show subpopulations

Gnomad AFR exome

AF:

0.000228

Gnomad AMR exome

AF:

0.0000365

Gnomad ASJ exome

AF:

0.000935

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000610

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000397

AC:

436

AN:

1097376

Hom.:

Cov.:

AF XY:

0.000405

AC XY:

147

AN XY:

362736

show subpopulations

Gnomad4 AFR exome

AF:

0.0000758

Gnomad4 AMR exome

AF:

0.000114

Gnomad4 ASJ exome

AF:

0.000981

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000481

Gnomad4 OTH exome

AF:

0.000130

GnomAD4 genome

AF:

0.000414

AC:

AN:

111184

Hom.:

Cov.:

AF XY:

0.000389

AC XY:

AN XY:

33404

show subpopulations

Gnomad4 AFR

AF:

0.000131

Gnomad4 AMR

AF:

0.000287

Gnomad4 ASJ

AF:

0.00114

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000679

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000680

Hom.:

Bravo

AF:

0.000495

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000692

AC:

ESP6500AA

AF:

0.000522

AC:

ESP6500EA

AF:

0.000446

AC:

ExAC

AF:

0.000272

AC:

EpiCase

AF:

0.000927

EpiControl

AF:

0.00142

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:13

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:6

Likely 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	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2023	LAMP2: BP4, BS2 -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 25, 2016	- -
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	Clinical Genetics, Academic Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

not specified

Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	Sep 14, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Dec 17, 2014	p.Thr196Ser in exon 5 of LAMP2: This variant has been reported in 2 males with a ccessory atrioventricular connections (Esposito 2009). Although it changes an a mino acid it is not expected to cause disease on its own for the following reaso ns: LAMP2 related disease is caused by a loss of function. Pathogenic missense variants are exceedingly rare (and those that have been reported lead to a loss of function by disrupting splicing). In addition, the Thr196Ser variant is prese nt at low frequency in large population data sets (30/67686 European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org) and has been reported in at least 2 apparently healthy males (Esposito 2009). Our l aboratory has detected this variant in a 46 year old female with DCM as well as her reportedly unaffected 72 year old mother and two males with isolated HCM (72 and 63 years old). In summary, it is possible that this variant contributes to disease but it is likely benign on its own. -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 28, 2018	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. -

Danon disease

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 29, 2024

- -

Cardiomyopathy

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

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

Jun 07, 2023

- -

Hypertrophic cardiomyopathy

Benign:1

Likely benign, criteria provided, single submitter

research

Agnes Ginges Centre for Molecular Cardiology, Centenary Institute

Mar 21, 2017

The LAMP2 Thr196Ser variant has been previously reported in DCM (Pugh TJ, et al., 2014), a compound heterozygous case of mild Danon Disease (Cetin H, et al., 2016), 2 patients with accessory atrioventicular connections and in 2 male controls (Esposito G, et al., 2009). The LAMP2 Thr196Ser variant is found in the Exome Aggregation Consortium dataset (http://exac.broadinstitute.org/) at an allele frequency >0.0002, which higher then expected for an inherited heart disease. We have identified the LAMP2 Thr196Ser variant in a male HCM proband who has a family history of disease (segregation not possible). This proband also carries a second variant; MYH6 Ser1414Phe. Computational tools are conflicting: SIFT and PolyPhen-2 predict LAMP2 Thr196Ser to be "deleterious" and "probably damaging", however MutationTaster predicts this variant to be a "polymorphism". In summary, the variant has been identified in controls and is seen at a high frequency in population databases, therefore we classify the LAMP2 Thr196Ser as "likely benign". Although it is unlikely that this variant causes disease on it's own, it's role as modifier can not be excluded. -

Cardiovascular phenotype

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 13, 2017

This alteration is classified as likely 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

Benign

0.12

CardioboostCm

Benign

0.023

BayesDel_addAF

Benign

-0.48

BayesDel_noAF

Benign

-0.57

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.32

.;T;.

FATHMM_MKL

Uncertain

0.88

LIST_S2

Benign

0.62

T;T;T

M_CAP

Uncertain

0.18

MetaRNN

Benign

0.080

T;T;T

MetaSVM

Benign

-0.78

MutationAssessor

Uncertain

2.6

M;M;M

MutationTaster

Benign

0.99

N;N;N;N;N

PrimateAI

Benign

0.39

PROVEAN

Uncertain

-3.1

D;D;D

REVEL

Benign

0.25

Sift

Benign

0.078

T;T;T

Sift4G

Benign

0.096

T;T;T

Polyphen

0.99, 0.96

.;D;D

Vest4

0.18

MVP

0.59

MPC

0.80

ClinPred

0.10

GERP RS

6.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.43

gMVP

0.67

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