chrX-120469114-A-C

Variant names:

• chrX-120469114-A-C
• rs397516745
• NM_002294.3:c.56T>G

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_002294.3(LAMP2):​c.56T>G​(p.Leu19Arg) variant causes a missense 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. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 23)
• Consequence: LAMP2 NM_002294.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.45
• Publications: 1 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: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.907

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LAMP2	NM_002294.3	c.56T>G	p.Leu19Arg	missense_variant	Exon 1 of 9	ENST00000200639.9	NP_002285.1
LAMP2	NM_001122606.1	c.56T>G	p.Leu19Arg	missense_variant	Exon 1 of 9		NP_001116078.1
LAMP2	NM_013995.2	c.56T>G	p.Leu19Arg	missense_variant	Exon 1 of 9		NP_054701.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LAMP2	ENST00000200639.9	c.56T>G	p.Leu19Arg	missense_variant	Exon 1 of 9	1	NM_002294.3	ENSP00000200639.4
LAMP2	ENST00000434600.6	c.56T>G	p.Leu19Arg	missense_variant	Exon 1 of 9	1		ENSP00000408411.2
LAMP2	ENST00000371335.4	c.56T>G	p.Leu19Arg	missense_variant	Exon 1 of 9	1		ENSP00000360386.4
LAMP2	ENST00000706600.1	c.56T>G	p.Leu19Arg	missense_variant	Exon 1 of 9			ENSP00000516464.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 23

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Feb 03, 2011

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant classified as Uncertain Significance - Favor Pathogenic. The Leu19Arg va riant has not been reported in the literature and has not been previously detect ed in over 2000 Caucasian chromosomes tested at our laboratory. This low freque ncy supports a pathogenic role as does the fact that it was detected in an indiv idual with a clinical presentation and family history consistent with Danon dise ase. However, although leucine (Leu) at position 19 is conserved among many mam malian species as well as more distant species (chicken, frog), one mammalian sp ecies (elephant) carries a different amino acid, reducing the likelihood that th e change is pathogenic. Importantly, pathogenic missense variants are very rare in the LAMP2 gene (most disease causing variants cause a loss of function). In summary, additional evidence is needed to determine the significance of this var iant. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.34
CardioboostCm	Benign	0.081
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.010
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.70	.;D;.
FATHMM_MKL	Benign	0.50	D
LIST_S2	Benign	0.80	T;T;T
M_CAP	Benign	0.077	D
MetaRNN	Pathogenic	0.91	D;D;D
MetaSVM	Benign	-0.45	T
MutationAssessor	Uncertain	2.4	M;M;M
PhyloP100		3.5
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-2.2	N;N;N
REVEL	Uncertain	0.32
Sift	Uncertain	0.0080	D;D;D
Sift4G	Benign	0.077	T;T;T
Polyphen		0.91, 0.97	.;P;D
Vest4		0.87
MutPred		0.73		Loss of stability (P = 0.0096);Loss of stability (P = 0.0096);Loss of stability (P = 0.0096);
MVP		0.90
MPC		1.0
ClinPred		0.96	D
GERP RS		4.1
PromoterAI		0.20	Neutral
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.0
Varity_R		0.40
gMVP		0.83
Mutation Taster		=8/92	disease causing

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: rs397516745; hg19: chrX-119602969;