rs1060502302

Variant names:

• chrX-120448978-CTC-TA
• rs1060502302
• NM_002294.3:c.546_548delGAGinsTA

Variant summary

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

The NM_002294.3(LAMP2):​c.546_548delGAGinsTA​(p.Ser183ThrfsTer59) variant causes a frameshift, missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 24)
• Consequence: LAMP2 NM_002294.3 frameshift, missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 3.07

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-120448978-CTC-TA is Pathogenic according to our data. Variant chrX-120448978-CTC-TA is described in ClinVar as [Pathogenic]. Clinvar id is 409221.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.546_548delGAGinsTA	p.Ser183ThrfsTer59	frameshift_variant, missense_variant	Exon 4 of 9	ENST00000200639.9	NP_002285.1
LAMP2	NM_001122606.1	c.546_548delGAGinsTA	p.Ser183ThrfsTer59	frameshift_variant, missense_variant	Exon 4 of 9		NP_001116078.1
LAMP2	NM_013995.2	c.546_548delGAGinsTA	p.Ser183ThrfsTer59	frameshift_variant, missense_variant	Exon 4 of 9		NP_054701.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LAMP2	ENST00000200639.9	c.546_548delGAGinsTA	p.Ser183ThrfsTer59	frameshift_variant, missense_variant	Exon 4 of 9	1	NM_002294.3	ENSP00000200639.4

Frequencies

GnomAD3 genomes Cov.: 24

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 24

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Danon disease Pathogenic:1

Nov 13, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

For these reasons, this variant has been classified as Pathogenic. While this particular variant has not been reported in the literature, loss-of-function variants in LAMP2 are known to be pathogenic (PMID: 21415759). This sequence change deletes 3 nucleotides and inserts 2 from exon 4 of the LAMP2 mRNA (c.546_548delinsTA), causing a frameshift at codon 183 This creates a premature translational stop signal (p.Ser183Thrfs*59) and is expected to result in an absent or disrupted protein product. -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs1060502302; hg19: chrX-119582833;