rs397516743

chrX-120456771-T-C

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PVS1_Moderate PP3 PP5_Very_Strong

The NM_002294.3(LAMP2):c.65-2A>G variant causes a splice acceptor change involving the alteration of a non-conserved nucleotide. 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
• Scores: Splicing: ADA: 0.9995
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 2.45

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 11 ACMG points.

• PVS1: Splicing variant, NOT destroyed by nmd, known LOF gene, truncates exone, which is 0.09570154 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.
• 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-120456771-T-C is Pathogenic according to our data. Variant chrX-120456771-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 44427.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-120456771-T-C is described in Lovd as [Pathogenic]. Variant chrX-120456771-T-C is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LAMP2	NM_002294.3	c.65-2A>G		splice_acceptor_variant		ENST00000200639.9
LAMP2	NM_001122606.1	c.65-2A>G		splice_acceptor_variant
LAMP2	NM_013995.2	c.65-2A>G		splice_acceptor_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LAMP2	ENST00000200639.9	c.65-2A>G		splice_acceptor_variant		1	NM_002294.3	P3
LAMP2	ENST00000371335.4	c.65-2A>G		splice_acceptor_variant		1		A1
LAMP2	ENST00000434600.6	c.65-2A>G		splice_acceptor_variant		1		A1
LAMP2	ENST00000706600.1	c.65-2A>G		splice_acceptor_variant

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 911333 Hom.: 0 Cov.: 16 AF XY: 0.00 AC XY: 0 AN XY: 237555

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:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Danon disease Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

May 21, 2010

- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

May 01, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.62	D
BayesDel_noAF	Benign	-0.67
Cadd	Uncertain	23
Dann	Benign	0.72
FATHMM_MKL	Benign	0.54	D
MutationTaster	Benign	1.0	D;D;D;D;D
GERP RS		3.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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

LitVar

Other links and lift over

dbSNP: rs397516743; hg19: chrX-119590626;