rs138991195

chrX-120447996-T-AchrX-120447996-T-C

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 0P and 7B. BP4_Moderate BP6 BS2

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). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T196A) has been classified as Uncertain significance.

• 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
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:13
• Conservation: PhyloP100: 1.45

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]

ACMG classification

Verdict is Benign. Variant got -7 ACMG points.

• 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, Uncertain_significance=1, Benign=1}. Variant chrX-120447996-T-A is described in Lovd as [Likely_benign].
• BS2: High Hemizygotes in GnomAd at 13 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LAMP2	NM_002294.3	c.586A>T	p.Thr196Ser	missense_variant	5/9	ENST00000200639.9
LAMP2	NM_001122606.1	c.586A>T	p.Thr196Ser	missense_variant	5/9
LAMP2	NM_013995.2	c.586A>T	p.Thr196Ser	missense_variant	5/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LAMP2	ENST00000200639.9	c.586A>T	p.Thr196Ser	missense_variant	5/9	1	NM_002294.3	P3

Frequencies

GnomAD3 genomes AF: 0.000414 AC: 46 AN: 111131 Hom.: 0 Cov.: 23 AF XY: 0.000390 AC XY: 13 AN XY: 33341

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: 61 AN: 183475 Hom.: 0 AF XY: 0.000471 AC XY: 32 AN XY: 67915

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.: 0 Cov.: 30 AF XY: 0.000405 AC XY: 147 AN XY: 362736

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: 46 AN: 111184 Hom.: 0 Cov.: 23 AF XY: 0.000389 AC XY: 13 AN XY: 33404

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.: 16

Bravo AF: 0.000495

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000692 AC: 2

ESP6500AA AF: 0.000522 AC: 2

ESP6500EA AF: 0.000446 AC: 3

ExAC AF: 0.000272 AC: 33

EpiCase AF: 0.000927

EpiControl AF: 0.00142

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:13

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:6

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	-	- -
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 DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 25, 2016	- -
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	-	- -

not specified Benign:3

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. -
Likely benign, criteria provided, single submitter	clinical testing	Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	Sep 14, 2016	- -

Danon disease Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

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	T
BayesDel_noAF	Benign	-0.57
Cadd	Benign	21
Dann	Uncertain	0.98
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Benign	0.62	T;T;T
M_CAP	Uncertain	0.18	D
MetaRNN	Benign	0.080	T;T;T
MetaSVM	Benign	-0.78	T
MutationAssessor	Uncertain	2.6	M;M;M
MutationTaster	Benign	0.99	N;N;N;N;N
PrimateAI	Benign	0.39	T
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	T
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

Other links and lift over

dbSNP: rs138991195; hg19: chrX-119581851;