rs727504600

Positions:

• chrX-120456712-CA-C

Variant summary

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

The ENST00000200639.9(LAMP2):​c.121del​(p.Cys41AlafsTer8) variant causes a frameshift change. 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: 22)
  • Exomes 𝑓: 0.0 (0 hom. 0 hem.)
  • Failed GnomAD Quality Control
• Consequence: LAMP2 ENST00000200639.9 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 5.70

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-120456712-CA-C is Pathogenic according to our data. Variant chrX-120456712-CA-C is described in ClinVar as [Pathogenic]. Clinvar id is 179062.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LAMP2	NM_002294.3	c.121del	p.Cys41AlafsTer8	frameshift_variant	2/9	ENST00000200639.9	NP_002285.1
LAMP2	NM_001122606.1	c.121del	p.Cys41AlafsTer8	frameshift_variant	2/9		NP_001116078.1
LAMP2	NM_013995.2	c.121del	p.Cys41AlafsTer8	frameshift_variant	2/9		NP_054701.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LAMP2	ENST00000200639.9	c.121del	p.Cys41AlafsTer8	frameshift_variant	2/9	1	NM_002294.3	ENSP00000200639	P3
LAMP2	ENST00000434600.6	c.121del	p.Cys41AlafsTer8	frameshift_variant	2/9	1		ENSP00000408411	A1
LAMP2	ENST00000371335.4	c.121del	p.Cys41AlafsTer8	frameshift_variant	2/9	1		ENSP00000360386	A1
LAMP2	ENST00000706600.1	c.121del	p.Cys41AlafsTer8	frameshift_variant	2/9			ENSP00000516464

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1080686 Hom.: 0 Cov.: 24 AF XY: 0.00 AC XY: 0 AN XY: 349648

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 22

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Danon disease Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Aug 09, 2013

The Cys41fs variant in LAMP2 has not been reported in individuals with cardiomyo pathy or Danon disease or in large population studies. This frameshift variant i s predicted to alter the protein?s amino acid sequence beginning at position 41 and lead to a premature termination codon 8 amino acids downstream. This alterat ion is then predicted to lead to a truncated or absent protein. Loss of function of the LAMP2 gene is an established disease mechanism in males with Danon disea se. In summary, this variant meets our criteria to be classified as pathogenic ( http://pcpgm.partners.org/LMM) based upon the predicted impact to the protein. -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs727504600; hg19: chrX-119590567;