rs397516747

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 2P and 6B. PM1BP4_ModerateBS2

The NM_002294.3(LAMP2):c.824A>G(p.Asn275Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000914 in 1,203,555 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 5 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N275D) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000063 ( 0 hom., 4 hem., cov: 22)

Exomes 𝑓: 0.0000037 ( 0 hom. 1 hem. )

Consequence

LAMP2
NM_002294.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:5

Conservation

PhyloP100: 0.728

Publications

1 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 -4 ACMG points.

PM1

In a glycosylation_site N-linked (GlcNAc...) asparagine (size 0) in uniprot entity LAMP2_HUMAN

BP4

Computational evidence support a benign effect (MetaRNN=0.20502105).

BS2

High Hemizygotes in GnomAd4 at 4 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LAMP2	NM_002294.3 link	c.824A>G	p.Asn275Ser	missense_variant	Exon 6 of 9	ENST00000200639.9	NP_002285.1	P13473-1
LAMP2	NM_001122606.1 link	c.824A>G	p.Asn275Ser	missense_variant	Exon 6 of 9		NP_001116078.1	P13473-3
LAMP2	NM_013995.2 link	c.824A>G	p.Asn275Ser	missense_variant	Exon 6 of 9		NP_054701.1	P13473-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LAMP2	ENST00000200639.9 link	c.824A>G	p.Asn275Ser	missense_variant	Exon 6 of 9	1	NM_002294.3	ENSP00000200639.4		P13473-1

Frequencies

GnomAD3 genomes

AF:

0.0000628

AC:

AN:

111493

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000196

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000956

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000109

AC:

AN:

183431

AF XY:

0.0000147

show subpopulations

Gnomad AFR exome

AF:

0.000152

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000366

AC:

AN:

1092062

Hom.:

Cov.:

AF XY:

0.00000280

AC XY:

AN XY:

357568

show subpopulations

African (AFR)

AF:

0.000114

AC:

AN:

26302

American (AMR)

AF:

0.00

AC:

AN:

35199

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19337

East Asian (EAS)

AF:

0.00

AC:

AN:

30180

South Asian (SAS)

AF:

0.00

AC:

AN:

54015

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40522

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4115

European-Non Finnish (NFE)

AF:

0.00000120

AC:

AN:

836497

Other (OTH)

AF:

0.00

AC:

AN:

45895

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.558

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000628

AC:

AN:

111493

Hom.:

Cov.:

AF XY:

0.000119

AC XY:

AN XY:

33665

show subpopulations

African (AFR)

AF:

0.000196

AC:

AN:

30591

American (AMR)

AF:

0.0000956

AC:

AN:

10458

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2645

East Asian (EAS)

AF:

0.00

AC:

AN:

3575

South Asian (SAS)

AF:

0.00

AC:

AN:

2689

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6005

Middle Eastern (MID)

AF:

0.00

AC:

AN:

239

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

53113

Other (OTH)

AF:

0.00

AC:

AN:

1496

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.592

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000416

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Uncertain:2

Dec 13, 2023

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: LAMP2 c.824A>G (p.Asn275Ser) results in a conservative amino acid change located in the Lysosome-associated membrane glycoprotein 2-like, luminal domains (IPR048528) of the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 9.1e-06 in 1203555 control chromosomes including 5 hemizygotes suggesting a benign role. c.824A>G has been reported in the literature in individuals affected with Cardiomyopathy (Walsh_2017). These report(s) do not provide unequivocal conclusions about association of the variant with Danon Disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication have been ascertained in the context of this evaluation (PMID: 27532257). Two submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly benign. -

May 04, 2009

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Danon disease

Uncertain:1

Aug 28, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 275 of the LAMP2 protein (p.Asn275Ser). This variant is present in population databases (rs397516747, gnomAD 0.02%), including at least one homozygous and/or hemizygous individual. This missense change has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 27532257). ClinVar contains an entry for this variant (Variation ID: 44438). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt LAMP2 protein function with a negative predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

not provided

Uncertain:1

Jul 31, 2024

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Observed in patients with HCM referred for genetic testing at GeneDx and in the published literature; however, one individual harbored additional pathogenic variants in other genes associated with cardiomyopathy (PMID: 27532257); In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 27532257) -

Cardiovascular phenotype

Uncertain:1

Aug 08, 2022

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.824A>G (p.N275S) alteration is located in exon 6 (coding exon 6) of the LAMP2 gene. This alteration results from a A to G substitution at nucleotide position 824, causing the asparagine (N) at amino acid position 275 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.089

CardioboostCm

Benign

0.0016

BayesDel_addAF

Benign

-0.62

BayesDel_noAF

Benign

-0.86

CADD

Benign

(source)

DANN

Benign

0.95

DEOGEN2

Benign

0.23

.;T;.

FATHMM_MKL

Benign

0.51

LIST_S2

Benign

0.76

T;T;T

M_CAP

Benign

0.018

MetaRNN

Benign

0.21

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.2

L;L;L

PhyloP100

0.73

PrimateAI

Benign

0.39

PROVEAN

Benign

-1.9

N;N;N

REVEL

Benign

0.029

Sift

Benign

0.34

T;T;T

Sift4G

Benign

0.69

T;T;T

Polyphen

0.024, 0.0010

.;B;B

Vest4

0.27

MutPred

0.32

Loss of sheet (P = 0.0357);Loss of sheet (P = 0.0357);Loss of sheet (P = 0.0357);

MVP

0.48

MPC

0.20

ClinPred

0.021

GERP RS

3.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.13

gMVP

0.24

Mutation Taster

=85/15

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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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rs397516747

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