chrX-120442615-A-C

Position:

• chrX-120442615-A-C

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_002294.3(LAMP2):​c.912T>G​(p.Tyr304Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. 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 Likely pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 22)
• Consequence: LAMP2 NM_002294.3 stop_gained
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 0.182

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 Pathogenic. Variant got 12 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-120442615-A-C is Pathogenic according to our data. Variant chrX-120442615-A-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 228269.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LAMP2	NM_002294.3	c.912T>G	p.Tyr304Ter	stop_gained	7/9	ENST00000200639.9
LAMP2	NM_001122606.1	c.912T>G	p.Tyr304Ter	stop_gained	7/9
LAMP2	NM_013995.2	c.912T>G	p.Tyr304Ter	stop_gained	7/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LAMP2	ENST00000200639.9	c.912T>G	p.Tyr304Ter	stop_gained	7/9	1	NM_002294.3	P3

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 22

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Danon disease Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

May 02, 2018

The p.Tyr304X variant in LAMP2 has not been previously reported in individuals w ith cardiomyopathy or Danon disease and was absent from large population studies . This nonsense variant leads to a premature termination codon at position 304, which is predicted to lead to a truncated or absent protein. Nonsense and other loss of function variants in LAMP2 are associated with Danon disease. In summary , although additional studies are required to fully establish its clinical signi ficance, the p.Tyr304X variant is likely pathogenic. ACMG/AMP Criteria applied: PVS1; PM2. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.62	D
BayesDel_noAF	Pathogenic	0.27
CADD	Pathogenic	35
DANN	Uncertain	1.0
FATHMM_MKL	Benign	0.15	N
MutationTaster	Benign	1.0	A;A;A;A;A
Vest4		0.82
GERP RS		0.99
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.16		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: rs876657648; hg19: chrX-119576470;