rs104894859

chrX-120441862-A-G

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_002294.3(LAMP2):c.961T>C(p.Trp321Arg) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 22)
• Consequence: LAMP2 NM_002294.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter P:1 U:1
• Conservation: PhyloP100: 6.97

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 Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.99

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LAMP2	NM_002294.3	c.961T>C	p.Trp321Arg	missense_variant	8/9	ENST00000200639.9
LAMP2	NM_001122606.1	c.961T>C	p.Trp321Arg	missense_variant	8/9
LAMP2	NM_013995.2	c.961T>C	p.Trp321Arg	missense_variant	8/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LAMP2	ENST00000200639.9	c.961T>C	p.Trp321Arg	missense_variant	8/9	1	NM_002294.3	P3

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 22

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Danon disease Pathogenic:1 Uncertain:1

Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Mar 31, 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 disruptive. ClinVar contains an entry for this variant (Variation ID: 9983). This missense change has been observed in individual(s) with clincial features of Danon disease (PMID: 15907287). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces tryptophan, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 321 of the LAMP2 protein (p.Trp321Arg). -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jun 01, 2005	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
CardioboostCm	Uncertain	0.50
BayesDel_addAF	Pathogenic	0.33	D
BayesDel_noAF	Pathogenic	0.23
Cadd	Pathogenic	26
Dann	Uncertain	1.0
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.82	T;T;T
M_CAP	Pathogenic	0.50	D
MetaRNN	Pathogenic	0.99	D;D;D
MetaSVM	Benign	-0.32	T
MutationAssessor	Pathogenic	3.0	M;M;M
MutationTaster	Benign	1.0	A;A;A;A;A
PrimateAI	Uncertain	0.79	T
PROVEAN	Pathogenic	-7.3	D;D;D
REVEL	Pathogenic	0.72
Sift	Uncertain	0.0020	D;D;D
Sift4G	Uncertain	0.0020	D;D;D
Polyphen		1.0	.;D;D
Vest4		0.92
MutPred		0.94		Gain of disorder (P = 0.0065);Gain of disorder (P = 0.0065);Gain of disorder (P = 0.0065);
MVP		0.98
MPC		1.2
ClinPred		1.0	D
GERP RS		5.8
Varity_R		0.99
gMVP		0.94

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs104894859; hg19: chrX-119575717;