rs878854484

chrX-120469147-G-AchrX-120469147-G-C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_002294.3(LAMP2):c.23C>T(p.Pro8Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000413 in 1,210,972 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 2 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/21 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. P8R) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0000089 ( 0 hom., 0 hem., cov: 23)

Exomes 𝑓: 0.0000036 ( 0 hom. 2 hem. )

Consequence

LAMP2
NM_002294.3 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.515

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 -2 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.16869316).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
LAMP2	NM_002294.3 linkuse as main transcript	c.23C>T	p.Pro8Leu	missense_variant	1/9	ENST00000200639.9
LAMP2	NM_001122606.1 linkuse as main transcript	c.23C>T	p.Pro8Leu	missense_variant	1/9
LAMP2	NM_013995.2 linkuse as main transcript	c.23C>T	p.Pro8Leu	missense_variant	1/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LAMP2	ENST00000200639.9 linkuse as main transcript	c.23C>T	p.Pro8Leu	missense_variant	1/9	1	NM_002294.3	P3	P13473-1
LAMP2	ENST00000434600.6 linkuse as main transcript	c.23C>T	p.Pro8Leu	missense_variant	1/9	1		A1	P13473-3
LAMP2	ENST00000371335.4 linkuse as main transcript	c.23C>T	p.Pro8Leu	missense_variant	1/9	1		A1	P13473-2
LAMP2	ENST00000706600.1 linkuse as main transcript	c.23C>T	p.Pro8Leu	missense_variant	1/9

Frequencies

GnomAD3 genomes

AF:

0.00000886

AC:

AN:

112849

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

34995

show subpopulations

Gnomad AFR

AF:

0.0000322

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000364

AC:

AN:

1098123

Hom.:

Cov.:

AF XY:

0.00000550

AC XY:

AN XY:

363507

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:

0.00000475

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000886

AC:

AN:

112849

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

34995

show subpopulations

Gnomad4 AFR

AF:

0.0000322

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:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Danon disease

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Sep 17, 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. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. ClinVar contains an entry for this variant (Variation ID: 239117). This variant has not been reported in the literature in individuals affected with LAMP2-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 8 of the LAMP2 protein (p.Pro8Leu). -

not provided

Uncertain:1

Uncertain significance, no assertion criteria provided

provider interpretation

Stanford Center for Inherited Cardiovascular Disease, Stanford University

Jan 27, 2016

- -

Cardiovascular phenotype

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 29, 2022

The p.P8L variant (also known as c.23C>T), located in coding exon 1 of the LAMP2 gene, results from a C to T substitution at nucleotide position 23. The proline at codon 8 is replaced by leucine, an amino acid with similar properties. This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.093

CardioboostCm

Benign

0.0029

BayesDel_addAF

Benign

-0.33

BayesDel_noAF

Benign

-0.71

Cadd

Benign

Dann

Uncertain

0.99

FATHMM_MKL

Benign

0.14

LIST_S2

Benign

0.73

T;T;T

M_CAP

Benign

0.015

MetaRNN

Benign

0.17

T;T;T

MetaSVM

Benign

-0.90

MutationAssessor

Benign

1.5

L;L;L

MutationTaster

Benign

1.0

N;N;N;N

PrimateAI

Benign

0.42

PROVEAN

Benign

-1.5

N;N;N

REVEL

Benign

0.086

Sift

Uncertain

0.0060

D;D;D

Sift4G

Benign

0.55

T;T;T

Polyphen

1.0

.;D;D

Vest4

0.19

MutPred

0.60

Gain of sheet (P = 0.039);Gain of sheet (P = 0.039);Gain of sheet (P = 0.039);

MVP

0.41

MPC

0.27

ClinPred

0.22

GERP RS

0.090

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.046

gMVP

0.64

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