Genetic Variant LAMP2:p.Arg53Pro (chrX-120456676-C-G) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_002294.3(LAMP2):c.158G>C(p.Arg53Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000194 in 1,030,673 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R53C) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 22)

Exomes 𝑓: 0.0000019 ( 0 hom. 0 hem. )

Consequence

LAMP2
NM_002294.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -4.44

Publications

0 publications found

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 Gene-Disease associations (from GenCC):

Danon disease
Inheritance: XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, G2P, Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Orphanet

LAMP2 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.14521855).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LAMP2	NM_002294.3 link	c.158G>C	p.Arg53Pro	missense_variant	Exon 2 of 9	ENST00000200639.9	NP_002285.1	P13473-1
LAMP2	NM_001122606.1 link	c.158G>C	p.Arg53Pro	missense_variant	Exon 2 of 9		NP_001116078.1	P13473-3
LAMP2	NM_013995.2 link	c.158G>C	p.Arg53Pro	missense_variant	Exon 2 of 9		NP_054701.1	P13473-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
LAMP2	ENST00000200639.9 link	c.158G>C	p.Arg53Pro	missense_variant	Exon 2 of 9	1	NM_002294.3	ENSP00000200639.4	P13473-1
LAMP2	ENST00000434600.6 link	c.158G>C	p.Arg53Pro	missense_variant	Exon 2 of 9	1		ENSP00000408411.2	P13473-3
LAMP2	ENST00000371335.4 link	c.158G>C	p.Arg53Pro	missense_variant	Exon 2 of 9	1		ENSP00000360386.4	P13473-2
LAMP2	ENST00000706600.1 link	c.158G>C	p.Arg53Pro	missense_variant	Exon 2 of 9			ENSP00000516464.1	A0A9L9PXQ4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000194

AC:

AN:

1030673

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

315891

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

25109

American (AMR)

AF:

0.00

AC:

AN:

34386

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

18764

East Asian (EAS)

AF:

0.00

AC:

AN:

29707

South Asian (SAS)

AF:

0.00

AC:

AN:

49993

European-Finnish (FIN)

AF:

0.00

AC:

AN:

39894

Middle Eastern (MID)

AF:

0.00

AC:

AN:

2936

European-Non Finnish (NFE)

AF:

0.00000254

AC:

AN:

786191

Other (OTH)

AF:

0.00

AC:

AN:

43693

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.26

CardioboostCm

Benign

0.0034

BayesDel_addAF

Benign

-0.40

BayesDel_noAF

Benign

-0.82

CADD

Benign

0.024

(source)

DANN

Benign

0.61

DEOGEN2

Benign

0.33

.;T;.

FATHMM_MKL

Benign

0.0073

LIST_S2

Benign

0.24

T;T;T

M_CAP

Benign

0.0043

MetaRNN

Benign

0.15

T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.69

N;N;N

PhyloP100

-4.4

PrimateAI

Benign

0.23

PROVEAN

Benign

-1.7

N;N;N

REVEL

Benign

0.027

Sift

Benign

0.28

T;T;T

Sift4G

Benign

0.27

T;T;T

Polyphen

0.0, 0.0010

.;B;B

Vest4

0.18

MutPred

0.45

Loss of catalytic residue at R53 (P = 0.0447);Loss of catalytic residue at R53 (P = 0.0447);Loss of catalytic residue at R53 (P = 0.0447);

MVP

0.31

MPC

0.36

ClinPred

0.20

GERP RS

-9.0

Varity_R

0.37

gMVP

0.85

Mutation Taster

=86/14

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over