Variant NM_002294.3:c.586A>G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM1BP4BS2

The NM_002294.3(LAMP2):c.586A>G(p.Thr196Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000638 in 1,097,378 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 4 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 23)

Exomes 𝑓: 0.0000064 ( 0 hom. 4 hem. )

Consequence

LAMP2
NM_002294.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.45

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 Likely_benign. Variant got -3 ACMG points.

PM1

In a glycosylation_site O-linked (GalNAc...) threonine (size 0) in uniprot entity LAMP2_HUMAN

BP4

Computational evidence support a benign effect (MetaRNN=0.38464025).

BS2

High Hemizygotes in GnomAdExome4 at 4 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LAMP2	NM_002294.3 link	c.586A>G	p.Thr196Ala	missense_variant	Exon 5 of 9	ENST00000200639.9	NP_002285.1	P13473-1
LAMP2	NM_001122606.1 link	c.586A>G	p.Thr196Ala	missense_variant	Exon 5 of 9		NP_001116078.1	P13473-3
LAMP2	NM_013995.2 link	c.586A>G	p.Thr196Ala	missense_variant	Exon 5 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.586A>G	p.Thr196Ala	missense_variant	Exon 5 of 9	1	NM_002294.3	ENSP00000200639.4		P13473-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000109

AC:

AN:

183475

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

67915

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000105

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000638

AC:

AN:

1097378

Hom.:

Cov.:

AF XY:

0.0000110

AC XY:

AN XY:

362736

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000924

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000238

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

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

Jun 15, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant has not been reported in the literature in individuals affected with LAMP2-related conditions. 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. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on LAMP2 protein function. This variant is present in population databases (rs138991195, gnomAD 0.01%), including at least one homozygous and/or hemizygous individual. This sequence change replaces threonine, which is neutral and polar, with alanine, which is neutral and non-polar, at codon 196 of the LAMP2 protein (p.Thr196Ala). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.086

CardioboostCm

Benign

0.063

BayesDel_addAF

Benign

-0.41

BayesDel_noAF

Benign

-0.63

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.33

.;T;.

FATHMM_MKL

Benign

0.72

LIST_S2

Benign

0.57

T;T;T

M_CAP

Uncertain

0.20

MetaRNN

Benign

0.38

T;T;T

MetaSVM

Benign

-0.82

MutationAssessor

Pathogenic

3.2

M;M;M

PrimateAI

Benign

0.38

PROVEAN

Uncertain

-3.7

D;D;D

REVEL

Benign

0.28

Sift

Benign

0.13

T;T;T

Sift4G

Uncertain

0.051

T;D;D

Polyphen

0.99, 0.99

.;D;D

Vest4

0.12

MutPred

0.61

Loss of glycosylation at T196 (P = 7e-04);Loss of glycosylation at T196 (P = 7e-04);Loss of glycosylation at T196 (P = 7e-04);

MVP

0.68

MPC

0.86

ClinPred

0.67

GERP RS

6.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.49

gMVP

0.83

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

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