rs145169006

Positions:

chrX-120447921-C-T

Variant summary

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

The NM_002294.3(LAMP2):c.661G>A(p.Gly221Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00221 in 1,209,052 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 848 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 0.0019 ( 0 hom., 62 hem., cov: 23)

Exomes 𝑓: 0.0022 ( 0 hom. 786 hem. )

Consequence

LAMP2
NM_002294.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:17

Conservation

PhyloP100: 3.07

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=0.02191636).

BP6

Variant X-120447921-C-T is Benign according to our data. Variant chrX-120447921-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 44434.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=5, Uncertain_significance=1, Benign=6}. Variant chrX-120447921-C-T is described in Lovd as [Pathogenic]. Variant chrX-120447921-C-T is described in Lovd as [Benign]. Variant chrX-120447921-C-T is described in Lovd as [Likely_benign].

BS2

High Hemizygotes in GnomAd4 at 62 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LAMP2	NM_002294.3 linkuse as main transcript	c.661G>A	p.Gly221Arg	missense_variant	5/9	ENST00000200639.9	NP_002285.1	P13473-1
LAMP2	NM_001122606.1 linkuse as main transcript	c.661G>A	p.Gly221Arg	missense_variant	5/9		NP_001116078.1	P13473-3
LAMP2	NM_013995.2 linkuse as main transcript	c.661G>A	p.Gly221Arg	missense_variant	5/9		NP_054701.1	P13473-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LAMP2	ENST00000200639.9 linkuse as main transcript	c.661G>A	p.Gly221Arg	missense_variant	5/9	1	NM_002294.3	ENSP00000200639.4		P13473-1

Frequencies

GnomAD3 genomes

AF:

0.00188

AC:

210

AN:

111755

Hom.:

Cov.:

AF XY:

0.00183

AC XY:

AN XY:

33915

show subpopulations

Gnomad AFR

AF:

0.000390

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00495

Gnomad ASJ

AF:

0.00453

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000999

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00231

Gnomad OTH

AF:

0.00334

GnomAD3 exomes

AF:

0.00155

AC:

285

AN:

183483

Hom.:

AF XY:

0.00131

AC XY:

AN XY:

67921

show subpopulations

Gnomad AFR exome

AF:

0.000608

Gnomad AMR exome

AF:

0.00175

Gnomad ASJ exome

AF:

0.00267

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00137

Gnomad NFE exome

AF:

0.00208

Gnomad OTH exome

AF:

0.00375

GnomAD4 exome

AF:

0.00224

AC:

2463

AN:

1097247

Hom.:

Cov.:

AF XY:

0.00217

AC XY:

786

AN XY:

362617

show subpopulations

Gnomad4 AFR exome

AF:

0.000152

Gnomad4 AMR exome

AF:

0.00230

Gnomad4 ASJ exome

AF:

0.00268

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000185

Gnomad4 FIN exome

AF:

0.00118

Gnomad4 NFE exome

AF:

0.00261

Gnomad4 OTH exome

AF:

0.00180

GnomAD4 genome

AF:

0.00188

AC:

210

AN:

111805

Hom.:

Cov.:

AF XY:

0.00182

AC XY:

AN XY:

33975

show subpopulations

Gnomad4 AFR

AF:

0.000389

Gnomad4 AMR

AF:

0.00494

Gnomad4 ASJ

AF:

0.00453

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000999

Gnomad4 NFE

AF:

0.00231

Gnomad4 OTH

AF:

0.00330

Alfa

AF:

0.00241

Hom.:

107

Bravo

AF:

0.00214

TwinsUK

AF:

0.00216

AC:

ALSPAC

AF:

0.00312

AC:

ESP6500AA

AF:

0.00104

AC:

ESP6500EA

AF:

0.00253

AC:

ExAC

AF:

0.00123

AC:

149

EpiCase

AF:

0.00169

EpiControl

AF:

0.00237

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:17

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Benign:5

Likely benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	May 26, 2015	p.Gly221Arg in LAMP2: This variant is not expected to have clinical significance because it has been identified in 0.2% (84/47999) of European chromosomes, incl uding 30 males, by the Exome Aggregation Consortium (ExAC, http://exac.broadins titute.org/; dbSNP rs145169006). -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	Oct 31, 2016	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 04, 2019	Variant summary: LAMP2 c.661G>A (p.Gly221Arg) results in a non-conservative amino acid change in the encoded protein sequence. Three of four in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0015 in 200310 control chromosomes in the gnomAD database, including 1 homozygote and 95 hemizygotes. The observed variant frequency is approximately 120 fold of the estimated maximal expected allele frequency for a pathogenic variant in LAMP2 causing Cardiomyopathy phenotype (1.3e-05), strongly suggesting that the variant is benign. The variant c.661G>A has been reported in the literature in patients with dilated (DCM) or hypertrophic (HCM) cardiomyopathies, however without evidence for causality (e.g. Mook 2013, Cecconi 2016, Mademont-Soler 2017). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as benign (2x)/likely benign(4x). Based on the evidence outlined above, the variant was classified as benign. -

Danon disease

Benign:5

Likely benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Aug 08, 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	Illumina Laboratory Services, Illumina	Apr 28, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign. -

not provided

Benign:4

Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
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	GeneDx	Sep 24, 2020	This variant is associated with the following publications: (PMID: 25091525, 23785128, 28074886, 27600940) -

Cardiomyopathy

Benign:2

Benign, criteria provided, single submitter	clinical testing	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	Feb 21, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Center for Advanced Laboratory Medicine, UC San Diego Health, University of California San Diego	May 14, 2019	- -

Intellectual disability

Uncertain:1

Uncertain significance, criteria provided, single submitter

research

Human Genetics Laboratory, State University of Rio de Janeiro

Apr 07, 2020

- -

Cardiovascular phenotype

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 15, 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

Pathogenic

0.66

BayesDel_addAF

Benign

-0.26

BayesDel_noAF

Benign

-0.15

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.49

.;T;.

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.90

D;D;D

M_CAP

Pathogenic

0.88

MetaRNN

Benign

0.022

T;T;T

MetaSVM

Uncertain

-0.24

MutationAssessor

Pathogenic

3.2

M;M;M

PrimateAI

Uncertain

0.49

PROVEAN

Pathogenic

-5.4

D;D;D

REVEL

Uncertain

0.41

Sift

Pathogenic

0.0

D;D;D

Sift4G

Uncertain

0.0030

D;D;D

Polyphen

1.0

.;D;D

Vest4

0.32

MutPred

0.83

Gain of solvent accessibility (P = 0.0584);Gain of solvent accessibility (P = 0.0584);Gain of solvent accessibility (P = 0.0584);

MVP

0.63

MPC

0.99

ClinPred

0.049

GERP RS

6.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.74

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