rs139633545

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP6BS2

The NM_002294.3(LAMP2):c.1142T>C(p.Val381Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000546 in 1,209,735 control chromosomes in the GnomAD database, including 1 homozygotes. There are 21 hemizygotes in GnomAD. 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. V381L) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00023 ( 0 hom., 7 hem., cov: 23)

Exomes 𝑓: 0.000036 ( 1 hom. 14 hem. )

Consequence

LAMP2
NM_002294.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:4

Conservation

PhyloP100: 8.51

Publications

4 publications found

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 Gene-Disease associations (from GenCC):

Danon disease
Inheritance: XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, G2P, Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Orphanet

LAMP2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -5 ACMG points.

BP6

Variant X-120431414-A-G is Benign according to our data. Variant chrX-120431414-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 180882.

BS2

High Hemizygotes in GnomAd4 at 7 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LAMP2	NM_002294.3 link	c.1142T>C	p.Val381Ala	missense_variant	Exon 9 of 9	ENST00000200639.9	NP_002285.1	P13473-1
LAMP2	NM_001122606.1 link	c.1094-2788T>C		intron_variant	Intron 8 of 8		NP_001116078.1	P13473-3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LAMP2	ENST00000200639.9 link	c.1142T>C	p.Val381Ala	missense_variant	Exon 9 of 9	1	NM_002294.3	ENSP00000200639.4		P13473-1

Frequencies

GnomAD3 genomes

AF:

0.000232

AC:

AN:

112272

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000711

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000555

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00133

GnomAD2 exomes

AF:

0.000116

AC:

AN:

181255

AF XY:

0.000119

show subpopulations

Gnomad AFR exome

AF:

0.00106

Gnomad AMR exome

AF:

0.0000730

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000361

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000364

AC:

AN:

1097463

Hom.:

Cov.:

AF XY:

0.0000386

AC XY:

AN XY:

362985

show subpopulations

African (AFR)

AF:

0.000265

AC:

AN:

26376

American (AMR)

AF:

0.0000568

AC:

AN:

35202

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19354

East Asian (EAS)

AF:

0.000132

AC:

AN:

30199

South Asian (SAS)

AF:

0.00

AC:

AN:

54119

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40525

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4134

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

841485

Other (OTH)

AF:

0.000586

AC:

AN:

46069

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.467

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000232

AC:

AN:

112272

Hom.:

Cov.:

AF XY:

0.000203

AC XY:

AN XY:

34446

show subpopulations

African (AFR)

AF:

0.000711

AC:

AN:

30946

American (AMR)

AF:

0.00

AC:

AN:

10583

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2650

East Asian (EAS)

AF:

0.000555

AC:

AN:

3606

South Asian (SAS)

AF:

0.00

AC:

AN:

2718

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6104

Middle Eastern (MID)

AF:

0.00

AC:

AN:

238

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

53233

Other (OTH)

AF:

0.00133

AC:

AN:

1507

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000186

Hom.:

Bravo

AF:

0.000253

ESP6500AA

AF:

0.00156

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000165

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:4

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Mar 23, 2015

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant classified as Uncertain Significance - Favor Benign. The p.Val381Ala var iant in LAMP2 has not been previously reported in individuals with cardiomyopath y or Danon disease, but has been identified in 0.1% (11/8513) African chromosome s, including 3 hemizygotes, by the Exome Aggregation Consortium (ExAC, http://ex ac.broadinstitute.org; dbSNP rs139633545). Computational prediction tools and co nservation analysis suggest that this variant may impact the protein, though thi s information is not predictive enough to determine pathogenicity. In summary, w hile the clinical significance of the p.Val381Ala variant is uncertain, its freq uency and presence in multiple hemizygous control individuals suggests that it is more likely to be benign. -

Cardiomyopathy

Uncertain:1

May 11, 2021

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

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Danon disease

Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

LAMP2-related disorder

Benign:1

Nov 17, 2020

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

not provided

Benign:1

Oct 02, 2020

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Cardiovascular phenotype

Benign:1

Jul 18, 2019

Ambry Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

Uncertain

0.52

CardioboostCm

Benign

0.062

BayesDel_addAF

Uncertain

0.081

BayesDel_noAF

Pathogenic

0.29

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.46

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.88

M_CAP

Pathogenic

0.44

MetaRNN

Uncertain

0.56

MetaSVM

Uncertain

-0.058

MutationAssessor

Pathogenic

3.1

PhyloP100

8.5

PROVEAN

Uncertain

-3.9

REVEL

Pathogenic

0.65

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.73

MVP

0.96

ClinPred

0.22

GERP RS

5.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.89

Mutation Taster

=81/19

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.14

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over