rs141574558

chrX-120449009-C-T

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 0P and 7B. BP4_ModerateBP6BS2

The NM_002294.3(LAMP2):c.517G>A(p.Val173Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000811 in 1,207,949 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 33 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. V173V) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000054 ( 0 hom., 3 hem., cov: 24)

Exomes 𝑓: 0.000084 ( 0 hom. 30 hem. )

Consequence

LAMP2
NM_002294.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:4

Conservation

PhyloP100: -1.03

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 Benign. Variant got -7 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.11145952).

BP6

Variant X-120449009-C-T is Benign according to our data. Variant chrX-120449009-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 44430.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=4, Uncertain_significance=1}.

BS2

High Hemizygotes in GnomAd at 3 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
LAMP2	NM_002294.3 linkuse as main transcript	c.517G>A	p.Val173Ile	missense_variant	4/9	ENST00000200639.9
LAMP2	NM_001122606.1 linkuse as main transcript	c.517G>A	p.Val173Ile	missense_variant	4/9
LAMP2	NM_013995.2 linkuse as main transcript	c.517G>A	p.Val173Ile	missense_variant	4/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LAMP2	ENST00000200639.9 linkuse as main transcript	c.517G>A	p.Val173Ile	missense_variant	4/9	1	NM_002294.3	P3	P13473-1

Frequencies

GnomAD3 genomes

AF:

0.0000536

AC:

AN:

112032

Hom.:

Cov.:

AF XY:

0.0000877

AC XY:

AN XY:

34206

show subpopulations

Gnomad AFR

AF:

0.00

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

GnomAD3 exomes

AF:

0.0000327

AC:

AN:

183241

Hom.:

AF XY:

0.0000886

AC XY:

AN XY:

67733

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:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000734

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000839

AC:

AN:

1095917

Hom.:

Cov.:

AF XY:

0.0000830

AC XY:

AN XY:

361347

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:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000102

Gnomad4 OTH exome

AF:

0.000130

GnomAD4 genome

AF:

0.0000536

AC:

AN:

112032

Hom.:

Cov.:

AF XY:

0.0000877

AC XY:

AN XY:

34206

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000113

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000142

Hom.:

Bravo

AF:

0.0000604

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000346

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000297

AC:

ExAC

AF:

0.0000412

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.000119

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:4

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 15, 2019	This variant is associated with the following publications: (PMID: 27532257) -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2024	LAMP2: BP4, BS2 -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Feb 28, 2014

Variant classified as Uncertain Significance - Favor Benign. The Val173Ile varia nt in LAMP2 has been previously reported by our laboratory in 2 individuals with HCM who were also carriers of a pathogenic variant in another HCM gene. It has also been identified in 2/6728 European American chromosomes by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu; dbSNP rs141574558). Computati onal prediction tools suggest that this variant may not impact the protein, thou gh this information is not predictive enough to rule out pathogenicity. Valine ( Val) at position 173 is not conserved in mammals or evolutionarily distant speci es, with one mammal (Chinese tree shrew) and some fish having this variant (Ile) at this position, further supporting that a change at this position may be tole rated. Furthermore, nearly all disease-causing variants in LAMP2 have been trunc ating, while this is a missense variant. In summary, although this data supports that the Val173Ile variant may be more likely benign, additional studies are ne eded to fully assess its clinical significance. -

Danon disease

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 21, 2024

- -

Cardiovascular phenotype

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 08, 2019

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

Benign

0.092

CardioboostCm

Benign

0.00069

BayesDel_addAF

Benign

-0.55

BayesDel_noAF

Benign

-0.85

Cadd

Benign

Dann

Benign

0.94

FATHMM_MKL

Benign

0.072

LIST_S2

Benign

0.77

T;T;T

M_CAP

Benign

0.012

MetaRNN

Benign

0.11

T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.3

L;L;L

MutationTaster

Benign

1.0

N;N;N;N;N

PrimateAI

Benign

0.34

PROVEAN

Benign

0.090

N;N;N

REVEL

Benign

0.089

Sift

Benign

0.39

T;T;T

Sift4G

Benign

0.55

T;T;T

Polyphen

0.20, 0.69

.;B;P

Vest4

0.086

MVP

0.34

MPC

0.29

ClinPred

0.043

GERP RS

3.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.058

gMVP

0.22

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