rs727503121

Positions:

• chrX-120456782-A-T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_002294.3(LAMP2):​c.65-13T>A variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000611 in 949,102 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 11 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.000036 (0 hom., 0 hem., cov: 22)
  • Exomes 𝑓: 0.000064 (0 hom. 11 hem.)
• Consequence: LAMP2 NM_002294.3 splice_polypyrimidine_tract, intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: -1.13

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 Benign. Variant got -9 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant X-120456782-A-T is Benign according to our data. Variant chrX-120456782-A-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 163818.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=1}. Variant chrX-120456782-A-T is described in Lovd as [Likely_benign].
• BS2: High Hemizygotes in GnomAdExome4 at 11 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LAMP2	NM_002294.3	c.65-13T>A		splice_polypyrimidine_tract_variant, intron_variant		ENST00000200639.9
LAMP2	NM_001122606.1	c.65-13T>A		splice_polypyrimidine_tract_variant, intron_variant
LAMP2	NM_013995.2	c.65-13T>A		splice_polypyrimidine_tract_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LAMP2	ENST00000200639.9	c.65-13T>A		splice_polypyrimidine_tract_variant, intron_variant		1	NM_002294.3	P3
LAMP2	ENST00000371335.4	c.65-13T>A		splice_polypyrimidine_tract_variant, intron_variant		1		A1
LAMP2	ENST00000434600.6	c.65-13T>A		splice_polypyrimidine_tract_variant, intron_variant		1		A1
LAMP2	ENST00000706600.1	c.65-13T>A		splice_polypyrimidine_tract_variant, intron_variant

Frequencies

GnomAD3 genomes AF: 0.0000358 AC: 4 AN: 111709 Hom.: 0 Cov.: 22 AF XY: 0.00 AC XY: 0 AN XY: 33903

Gnomad AFR AF: 0.0000326

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000564

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000221 AC: 3 AN: 135641 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 39957

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000529

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000645 AC: 54 AN: 837393 Hom.: 0 Cov.: 14 AF XY: 0.0000520 AC XY: 11 AN XY: 211409

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000318

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: 0.0000852

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000358 AC: 4 AN: 111709 Hom.: 0 Cov.: 22 AF XY: 0.00 AC XY: 0 AN XY: 33903

Gnomad4 AFR AF: 0.0000326

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000564

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000340

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:1 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 30, 2017	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Nov 03, 2014	The c.65-13T>A variant in LAMP2 has not been previously reported in individuals with cardiomyopathy. Data from large population studies are insufficient to asse ss the frequency of this variant. This variant is located in the 3' splice regio n. Computational tools do not suggest an impact to splicing. However, this infor mation is not predictive enough to determine pathogenicity. In summary, the clin ical significance of the c.65-13T>A variant is uncertain. -

Danon disease Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 18, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.056
DANN	Benign	0.49
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs727503121; hg19: chrX-119590637;