X-120442669-GA-GAA

Variant names:

• chrX-120442669-G-GA
• rs746330494
• NM_002294.3:c.865-8dupT

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP6_Moderate BS2

The NM_002294.3(LAMP2):​c.865-8dupT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000655 in 1,069,215 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 3 hemizygotes in GnomAD. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: not found (cov: 22)
  • Exomes 𝑓: 0.0000065 (0 hom. 3 hem.)
• Consequence: LAMP2 NM_002294.3 splice_region, intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 2.87
• Publications: 0 publications found

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]

LAMP2 Gene-Disease associations (from GenCC):

• Danon disease

  Inheritance: XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, G2P, Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -6 ACMG points.

• BP6: Variant X-120442669-G-GA is Benign according to our data. Variant chrX-120442669-G-GA is described in ClinVar as Likely_benign. ClinVar VariationId is 415503.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Hemizygotes in GnomAdExome4 at 3 XL gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002294.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LAMP2	NM_002294.3	MANE Select	c.865-8dupT		splice_region intron	N/A	NP_002285.1
	LAMP2	NM_001122606.1		c.865-8dupT		splice_region intron	N/A	NP_001116078.1
	LAMP2	NM_013995.2		c.865-8dupT		splice_region intron	N/A	NP_054701.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LAMP2	ENST00000200639.9	TSL:1 MANE Select	c.865-8_865-7insT		splice_region intron	N/A	ENSP00000200639.4
	LAMP2	ENST00000434600.6	TSL:1	c.865-8_865-7insT		splice_region intron	N/A	ENSP00000408411.2
	LAMP2	ENST00000371335.4	TSL:1	c.865-8_865-7insT		splice_region intron	N/A	ENSP00000360386.4

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD2 exomes AF: 0.0000438 AC: 8 AN: 182769 AF XY: 0.0000594

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000292

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000655 AC: 7 AN: 1069215 Hom.: 0 Cov.: 27 AF XY: 0.00000891 AC XY: 3 AN XY: 336513

African (AFR) AF: 0.00 AC: 0 AN: 25876

American (AMR) AF: 0.000199 AC: 7 AN: 35158

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19197

East Asian (EAS) AF: 0.00 AC: 0 AN: 30103

South Asian (SAS) AF: 0.00 AC: 0 AN: 53412

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40202

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4060

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 816047

Other (OTH) AF: 0.00 AC: 0 AN: 45160

GnomAD4 genome Cov.: 22

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Danon disease Benign:1

Oct 10, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		2.9
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs746330494; hg19: chrX-119576524;