X-120439198-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_StrongBS2

The ENST00000371335.4(LAMP2):c.1189G>A(p.Val397Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000464 in 1,206,685 control chromosomes in the GnomAD database, including 1 homozygotes. There are 19 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/17 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. V397L) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00012 ( 0 hom., 6 hem., cov: 23)

Exomes 𝑓: 0.000039 ( 1 hom. 13 hem. )

Consequence

LAMP2
ENST00000371335.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.200

Publications

3 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: Benign. The variant received -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.04498282).

BS2

High Hemizygotes in GnomAd4 at 6 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
LAMP2	NM_002294.3 link	c.1093+2532G>A		intron_variant	Intron 8 of 8	ENST00000200639.9	NP_002285.1
LAMP2	NM_013995.2 link	c.1189G>A	p.Val397Ile	missense_variant	Exon 9 of 9		NP_054701.1
LAMP2	NM_001122606.1 link	c.1093+2532G>A		intron_variant	Intron 8 of 8		NP_001116078.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LAMP2	ENST00000200639.9 link	c.1093+2532G>A		intron_variant	Intron 8 of 8	1	NM_002294.3	ENSP00000200639.4

Frequencies

GnomAD3 genomes

AF:

0.000116

AC:

AN:

111775

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000228

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.000113

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000109

AC:

AN:

183347

AF XY:

0.00

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:

0.0000393

AC:

AN:

1094910

Hom.:

Cov.:

AF XY:

0.0000361

AC XY:

AN XY:

360396

show subpopulations

African (AFR)

AF:

0.0000759

AC:

AN:

26336

American (AMR)

AF:

0.00

AC:

AN:

35196

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19349

East Asian (EAS)

AF:

0.00

AC:

AN:

30142

South Asian (SAS)

AF:

0.00

AC:

AN:

54078

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40517

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4126

European-Non Finnish (NFE)

AF:

0.0000477

AC:

AN:

839177

Other (OTH)

AF:

0.0000217

AC:

AN:

45989

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.470

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:

0.000116

AC:

AN:

111775

Hom.:

Cov.:

AF XY:

0.000177

AC XY:

AN XY:

33967

show subpopulations

African (AFR)

AF:

0.000228

AC:

AN:

30751

American (AMR)

AF:

0.00

AC:

AN:

10465

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2650

East Asian (EAS)

AF:

0.00

AC:

AN:

3594

South Asian (SAS)

AF:

0.00

AC:

AN:

2701

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6016

Middle Eastern (MID)

AF:

0.00

AC:

AN:

237

European-Non Finnish (NFE)

AF:

0.000113

AC:

AN:

53177

Other (OTH)

AF:

0.00

AC:

AN:

1501

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.468

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:

0.000142

Hom.:

Bravo

AF:

0.000178

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Danon disease

Uncertain:1

Sep 22, 2016

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

In summary, this variant is a rare missense change that is not predicted to affect protein function. There is no indication that it causes disease, but the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance. General algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD), suggest that this missense change is likely to be tolerated. However, these predictions have not been confirmed by published functional studies. This variant is present in population databases (rs730880488, ExAC 0.02%) but has not been reported in the literature in individuals with a LAMP2-related disease. This sequence change replaces valine with isoleucine at codon 397 of the LAMP2 protein (p.Val397Ile). The valine residue is weakly conserved and there is a small physicochemical difference between valine and isoleucine. The LAMP2 gene has multiple clinically relevant isoforms. The p.Val397Ile variant occurs in alternate transcript NM_013995.2, which corresponds to position c.1093+2532G>A in NM_002294.2 , the primary transcript listed in the Methods. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.080

BayesDel_addAF

Benign

-0.60

BayesDel_noAF

Benign

-0.84

CADD

Benign

(source)

DANN

Benign

0.91

FATHMM_MKL

Benign

0.66

LIST_S2

Benign

0.067

M_CAP

Benign

0.0055

MetaRNN

Benign

0.045

MetaSVM

Benign

-1.0

PhyloP100

0.20

PROVEAN

Benign

0.71

REVEL

Benign

0.031

Sift

Benign

0.24

Sift4G

Benign

0.27

Polyphen

0.0

Vest4

0.058

MVP

0.32

ClinPred

0.061

GERP RS

2.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=91/9

polymorphism

(source)

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

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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