rs397516735

chrX-120456676-C-AchrX-120456676-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_002294.3(LAMP2):c.158G>T(p.Arg53Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000291 in 1,030,671 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. 15/21 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. R53C) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 22)
  • Exomes 𝑓: 0.0000029 (0 hom. 0 hem.)
• Consequence: LAMP2 NM_002294.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -4.44

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]

ACMG classification

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=0.16091472).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LAMP2	NM_002294.3	c.158G>T	p.Arg53Leu	missense_variant	2/9	ENST00000200639.9
LAMP2	NM_001122606.1	c.158G>T	p.Arg53Leu	missense_variant	2/9
LAMP2	NM_013995.2	c.158G>T	p.Arg53Leu	missense_variant	2/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LAMP2	ENST00000200639.9	c.158G>T	p.Arg53Leu	missense_variant	2/9	1	NM_002294.3	P3
LAMP2	ENST00000434600.6	c.158G>T	p.Arg53Leu	missense_variant	2/9	1		A1
LAMP2	ENST00000371335.4	c.158G>T	p.Arg53Leu	missense_variant	2/9	1		A1
LAMP2	ENST00000706600.1	c.158G>T	p.Arg53Leu	missense_variant	2/9

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome AF: 0.00000291 AC: 3 AN: 1030671 Hom.: 0 Cov.: 19 AF XY: 0.00 AC XY: 0 AN XY: 315889

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: 0.00000382

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 22

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Danon disease Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jul 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. 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. 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 arginine, which is basic and polar, with leucine, which is neutral and non-polar, at codon 53 of the LAMP2 protein (p.Arg53Leu). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
CardioboostCm	Benign	0.0034
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.84
Cadd	Benign	0.013
Dann	Benign	0.82
FATHMM_MKL	Benign	0.012	N
LIST_S2	Benign	0.57	T;T;T
M_CAP	Benign	0.0072	T
MetaRNN	Benign	0.16	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.4	L;L;L
MutationTaster	Benign	1.0	N;N;N;N;N
PrimateAI	Benign	0.23	T
PROVEAN	Benign	-2.0	N;N;N
REVEL	Benign	0.056
Sift	Benign	0.29	T;T;T
Sift4G	Benign	0.29	T;T;T
Polyphen		0.047, 0.29	.;B;B
Vest4		0.11
MutPred		0.46		Loss of catalytic residue at R53 (P = 0.0393);Loss of catalytic residue at R53 (P = 0.0393);Loss of catalytic residue at R53 (P = 0.0393);
MVP		0.27
MPC		0.35
ClinPred		0.29	T
GERP RS		-9.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.10
gMVP		0.51

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

Other links and lift over

dbSNP: rs397516735; hg19: chrX-119590531;