X-120446300-C-T

Variant names:

• chrX-120446300-C-T
• NM_002294.3:c.864+5G>A

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Moderate PP5_Moderate

The NM_002294.3(LAMP2):​c.864+5G>A variant causes a splice region, intron change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 22)
• Consequence: LAMP2 NM_002294.3 splice_region, intron
• Scores: Splicing: ADA: 0.9998
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 4.53

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: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant X-120446300-C-T is Pathogenic according to our data. Variant chrX-120446300-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 3251932.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LAMP2	NM_002294.3	c.864+5G>A		splice_region_variant, intron_variant	Intron 6 of 8	ENST00000200639.9	NP_002285.1
LAMP2	NM_001122606.1	c.864+5G>A		splice_region_variant, intron_variant	Intron 6 of 8		NP_001116078.1
LAMP2	NM_013995.2	c.864+5G>A		splice_region_variant, intron_variant	Intron 6 of 8		NP_054701.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LAMP2	ENST00000200639.9	c.864+5G>A		splice_region_variant, intron_variant	Intron 6 of 8	1	NM_002294.3	ENSP00000200639.4

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

Dec 01, 2023

Department of Cardiovascular Medicine, The University of Tokyo, Graduate School of Medicine

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing;research

A case report (PMID:38246647) showed the exon 6 skipping in LAMP2 gene with human tissues and demonstrated LAMP2 deficiency in cardiac and skeletal muscle. Exon 6 skipping in LAMP2 gene is a many reported cause of Danon disease in human (PMID:37277924, PMID:24691104, PMID:21161685, PMID: 23262972, PMID:29463847, PMID:28822614, PMID: 9536098, PMID:10972294, DOI:10.1016/j.genrep.2019.100564), and it was also confirmed in mice model (PMID: 34459252). This variant was confirmed to cause exon 6 skipping (PS3). This variant is absent in databases, including ExAC, gnomAD Global AF, gnomAD EAS AF, TMM 54K JPN AF (PM2 Supporting). This variant cause exon 6 skipping resulting in protein length changing (PM4), and the patient's phenotype was highly specific for Danon disease (PP4). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.21
CADD	Benign	17
DANN	Benign	0.96

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.97
SpliceAI score (max)		0.99		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.99		Position offset: 5

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chrX-119580155;