rs397516741

Positions:

chrX-120455455-G-A

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The NM_002294.3(LAMP2):c.299C>T(p.Ala100Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000489 in 1,207,540 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 16 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 Likely benign (★★).

Frequency

Genomes: 𝑓 0.000045 ( 0 hom., 3 hem., cov: 20)

Exomes 𝑓: 0.000049 ( 0 hom. 13 hem. )

Consequence

LAMP2
NM_002294.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 2.09

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 -16 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.026088).

BP6

Variant X-120455455-G-A is Benign according to our data. Variant chrX-120455455-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 44424.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High Hemizygotes in GnomAd4 at 3 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LAMP2	NM_002294.3 linkuse as main transcript	c.299C>T	p.Ala100Val	missense_variant	3/9	ENST00000200639.9	NP_002285.1	P13473-1
LAMP2	NM_001122606.1 linkuse as main transcript	c.299C>T	p.Ala100Val	missense_variant	3/9		NP_001116078.1	P13473-3
LAMP2	NM_013995.2 linkuse as main transcript	c.299C>T	p.Ala100Val	missense_variant	3/9		NP_054701.1	P13473-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
LAMP2	ENST00000200639.9 linkuse as main transcript	c.299C>T	p.Ala100Val	missense_variant	3/9	1	NM_002294.3	ENSP00000200639.4	P13473-1
LAMP2	ENST00000434600.6 linkuse as main transcript	c.299C>T	p.Ala100Val	missense_variant	3/9	1		ENSP00000408411.2	P13473-3
LAMP2	ENST00000371335.4 linkuse as main transcript	c.299C>T	p.Ala100Val	missense_variant	3/9	1		ENSP00000360386.4	P13473-2
LAMP2	ENST00000706600.1 linkuse as main transcript	c.299C>T	p.Ala100Val	missense_variant	3/9			ENSP00000516464.1	A0A9L9PXQ4

Frequencies

GnomAD3 genomes

AF:

0.0000451

AC:

AN:

110897

Hom.:

Cov.:

AF XY:

0.0000906

AC XY:

AN XY:

33121

show subpopulations

Gnomad AFR

AF:

0.0000329

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000378

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000566

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000491

AC:

AN:

183472

Hom.:

AF XY:

0.0000736

AC XY:

AN XY:

67916

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:

0.0000977

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000492

AC:

AN:

1096590

Hom.:

Cov.:

AF XY:

0.0000359

AC XY:

AN XY:

361970

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:

0.0000185

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000607

Gnomad4 OTH exome

AF:

0.0000434

GnomAD4 genome

AF:

0.0000451

AC:

AN:

110950

Hom.:

Cov.:

AF XY:

0.0000904

AC XY:

AN XY:

33184

show subpopulations

Gnomad4 AFR

AF:

0.0000328

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000380

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000566

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000340

ExAC

AF:

0.0000494

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.000119

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Apr 11, 2012	Ala100Val in 3 of LAMP2: This variant is not expected to have clinical significa nce because it has been previously reported in a phenotypically unaffected male who was hemizygous for this variant. Ala100Val in 3 of LAMP2 (allele frequency = n/a) -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 14, 2017	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Danon disease

Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 18, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Aug 17, 2021	- -

not provided

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Jun 01, 2023

LAMP2: BP4, BS2 -

Cardiovascular phenotype

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 18, 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

0.071

CardioboostCm

Benign

0.0021

BayesDel_addAF

Benign

-0.67

BayesDel_noAF

Benign

-1.0

CADD

Benign

4.1

DANN

Benign

0.17

DEOGEN2

Benign

0.26

.;T;.

FATHMM_MKL

Benign

0.0037

LIST_S2

Benign

0.80

T;T;T

M_CAP

Benign

0.0029

MetaRNN

Benign

0.026

T;T;T

MetaSVM

Benign

-0.98

MutationAssessor

Benign

-1.8

N;N;N

PrimateAI

Benign

0.27

PROVEAN

Benign

2.0

N;N;N

REVEL

Benign

0.023

Sift

Benign

1.0

T;T;T

Sift4G

Benign

1.0

T;T;T

Polyphen

0.0010, 0.0020

.;B;B

Vest4

0.049

MutPred

0.34

Gain of methylation at K104 (P = 0.0916);Gain of methylation at K104 (P = 0.0916);Gain of methylation at K104 (P = 0.0916);

MVP

0.15

MPC

0.25

ClinPred

0.016

GERP RS

2.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.031

gMVP

0.28

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