rs397516743

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1_ModeratePM2PP5_Very_Strong

The NM_002294.3(LAMP2):c.65-2A>G variant causes a splice acceptor, intron 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. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★).

Frequency

Genomes: not found (cov: 22)

Exomes 𝑓: 0.0 ( 0 hom. 0 hem. )

Failed GnomAD Quality Control

Consequence

LAMP2
NM_002294.3 splice_acceptor, intron

Scores

Splicing: ADA: 0.9995

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:2

Conservation

PhyloP100: 2.45

Publications

3 publications found

Variant links:

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

LAMP2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 12 ACMG points.

PVS1

Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.09651257 fraction of the gene. Cryptic splice site detected, with MaxEntScore 3.9, offset of 39, new splice context is: attggaacttaatttgacAGatt. Cryptic site results in inframe change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant X-120456771-T-C is Pathogenic according to our data. Variant chrX-120456771-T-C is described in ClinVar as Pathogenic. ClinVar VariationId is 44427.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
LAMP2	NM_002294.3	MANE Select	c.65-2A>G	splice_acceptor intron	N/A	NP_002285.1
LAMP2	NM_001122606.1		c.65-2A>G	splice_acceptor intron	N/A	NP_001116078.1
LAMP2	NM_013995.2		c.65-2A>G	splice_acceptor intron	N/A	NP_054701.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
LAMP2	ENST00000200639.9	TSL:1 MANE Select	c.65-2A>G	splice_acceptor intron	N/A	ENSP00000200639.4
LAMP2	ENST00000434600.6	TSL:1	c.65-2A>G	splice_acceptor intron	N/A	ENSP00000408411.2
LAMP2	ENST00000371335.4	TSL:1	c.65-2A>G	splice_acceptor intron	N/A	ENSP00000360386.4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0;AS_VQSR

AF:

0.00

AC:

AN:

911333

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

237555

African (AFR)

AF:

0.00

AC:

AN:

22622

American (AMR)

AF:

0.00

AC:

AN:

32602

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

17721

East Asian (EAS)

AF:

0.00

AC:

AN:

28507

South Asian (SAS)

AF:

0.00

AC:

AN:

43789

European-Finnish (FIN)

AF:

0.00

AC:

AN:

38564

Middle Eastern (MID)

AF:

0.00

AC:

AN:

2753

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

685415

Other (OTH)

AF:

0.00

AC:

AN:

39360

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Danon disease

Pathogenic:1

May 21, 2010

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

not provided

Pathogenic:1

May 01, 2020

CeGaT Center for Human Genetics Tuebingen

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.62

BayesDel_noAF

Benign

-0.67

CADD

Uncertain

(source)

DANN

Benign

0.72

FATHMM_MKL

Benign

0.54

PhyloP100

2.5

GERP RS

3.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Mutation Taster

=0/100

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.73

SpliceAI score (max)

0.98

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.38

Position offset: -41

DS_AL_spliceai

0.98

Position offset: -2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over