rs778193991

Positions:

chrX-120455540-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_002294.3(LAMP2):c.214G>A(p.Val72Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000456 in 1,095,662 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: not found (cov: 21)

Exomes 𝑓: 0.0000046 ( 0 hom. 1 hem. )

Consequence

LAMP2
NM_002294.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: 0.644

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 Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.2451089).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
LAMP2	NM_002294.3 linkuse as main transcript	c.214G>A	p.Val72Met	missense_variant	3/9	ENST00000200639.9
LAMP2	NM_001122606.1 linkuse as main transcript	c.214G>A	p.Val72Met	missense_variant	3/9
LAMP2	NM_013995.2 linkuse as main transcript	c.214G>A	p.Val72Met	missense_variant	3/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LAMP2	ENST00000200639.9 linkuse as main transcript	c.214G>A	p.Val72Met	missense_variant	3/9	1	NM_002294.3	P3	P13473-1
LAMP2	ENST00000434600.6 linkuse as main transcript	c.214G>A	p.Val72Met	missense_variant	3/9	1		A1	P13473-3
LAMP2	ENST00000371335.4 linkuse as main transcript	c.214G>A	p.Val72Met	missense_variant	3/9	1		A1	P13473-2
LAMP2	ENST00000706600.1 linkuse as main transcript	c.214G>A	p.Val72Met	missense_variant	3/9

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000545

AC:

AN:

183403

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

67857

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:

0.0000524

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000456

AC:

AN:

1095662

Hom.:

Cov.:

AF XY:

0.00000277

AC XY:

AN XY:

361048

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:

0.0000370

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.0000652

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000756

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

May 02, 2017

The p.Val72Met variant in LAMP2 has not been previously reported in individuals with cardiomyopathy, but has been identified in 1/19131 South Asian chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org/; d bSNP rs778193991). Computational prediction tools and conservation analysis do n ot provide strong support for or against an impact to the protein. In summary, t he clinical significance of the p.Val72Met variant is uncertain. -

Danon disease

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Dec 15, 2022

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) performed at Invitae indicates that this missense variant is expected to disrupt LAMP2 protein function. ClinVar contains an entry for this variant (Variation ID: 505795). This variant has not been reported in the literature in individuals affected with LAMP2-related conditions. This variant is present in population databases (rs778193991, gnomAD 0.005%), including at least one homozygous and/or hemizygous individual. This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 72 of the LAMP2 protein (p.Val72Met). -

Primary dilated cardiomyopathy

Uncertain:1

Uncertain significance, criteria provided, single submitter

research

Genetics and Genomics Program, Sidra Medicine

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

CardioboostCm

Benign

0.056

BayesDel_addAF

Benign

-0.50

BayesDel_noAF

Benign

-0.81

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.62

.;D;.

FATHMM_MKL

Benign

0.049

LIST_S2

Uncertain

0.89

D;D;D

M_CAP

Uncertain

0.16

MetaRNN

Benign

0.25

T;T;T

MetaSVM

Benign

-0.92

MutationAssessor

Benign

1.8

L;L;L

MutationTaster

Benign

1.0

N;N;N;N;N

PrimateAI

Benign

0.36

PROVEAN

Benign

-2.0

N;N;N

REVEL

Benign

0.062

Sift

Uncertain

0.011

D;D;D

Sift4G

Uncertain

0.013

D;D;D

Polyphen

1.0, 1.0

.;D;D

Vest4

0.064

MutPred

0.48

Loss of catalytic residue at V72 (P = 0.0055);Loss of catalytic residue at V72 (P = 0.0055);Loss of catalytic residue at V72 (P = 0.0055);

MVP

0.55

MPC

0.77

ClinPred

0.63

GERP RS

2.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.11

gMVP

0.68

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