rs397516735

Variant names:

• chrX-120456676-C-A
• rs397516735
• NM_002294.3:c.158G>T

Your query was ambiguous. Multiple possible variants found:

• chrX-120456676-C-A
• chrX-120456676-C-G
• chrX-120456676-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 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. 16/22 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
• Publications: 1 publications found

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

ACMG classification

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=0.16091472).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LAMP2	NM_002294.3	c.158G>T	p.Arg53Leu	missense_variant	Exon 2 of 9	ENST00000200639.9	NP_002285.1
LAMP2	NM_001122606.1	c.158G>T	p.Arg53Leu	missense_variant	Exon 2 of 9		NP_001116078.1
LAMP2	NM_013995.2	c.158G>T	p.Arg53Leu	missense_variant	Exon 2 of 9		NP_054701.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LAMP2	ENST00000200639.9	c.158G>T	p.Arg53Leu	missense_variant	Exon 2 of 9	1	NM_002294.3	ENSP00000200639.4
LAMP2	ENST00000434600.6	c.158G>T	p.Arg53Leu	missense_variant	Exon 2 of 9	1		ENSP00000408411.2
LAMP2	ENST00000371335.4	c.158G>T	p.Arg53Leu	missense_variant	Exon 2 of 9	1		ENSP00000360386.4
LAMP2	ENST00000706600.1	c.158G>T	p.Arg53Leu	missense_variant	Exon 2 of 9			ENSP00000516464.1

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

African (AFR) AF: 0.00 AC: 0 AN: 25109

American (AMR) AF: 0.00 AC: 0 AN: 34386

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18764

East Asian (EAS) AF: 0.00 AC: 0 AN: 29707

South Asian (SAS) AF: 0.00 AC: 0 AN: 49992

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 39894

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2936

European-Non Finnish (NFE) AF: 0.00000382 AC: 3 AN: 786190

Other (OTH) AF: 0.00 AC: 0 AN: 43693

GnomAD4 genome Cov.: 22

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Danon disease Uncertain:1

Jul 15, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 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). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with LAMP2-related conditions. 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. -

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
DEOGEN2	Benign	0.40	.;T;.
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
PhyloP100		-4.4
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
Mutation Taster		=95/5	polymorphism

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

Other links and lift over

dbSNP: rs397516735; hg19: chrX-119590531;