X-120448001-G-A

Variant names:

• chrX-120448001-G-A
• rs1033442580
• NM_002294.3:c.581C>T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001122606.1(LAMP2):​c.581C>T​(p.Thr194Ile) 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 benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T194N) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 23)
• Consequence: LAMP2 NM_001122606.1 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 0.371
• 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: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.27231592).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001122606.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LAMP2	NM_002294.3	MANE Select	c.581C>T	p.Thr194Ile	missense	Exon 5 of 9	NP_002285.1
	LAMP2	NM_001122606.1		c.581C>T	p.Thr194Ile	missense	Exon 5 of 9	NP_001116078.1
	LAMP2	NM_013995.2		c.581C>T	p.Thr194Ile	missense	Exon 5 of 9	NP_054701.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LAMP2	ENST00000200639.9	TSL:1 MANE Select	c.581C>T	p.Thr194Ile	missense	Exon 5 of 9	ENSP00000200639.4
	LAMP2	ENST00000434600.6	TSL:1	c.581C>T	p.Thr194Ile	missense	Exon 5 of 9	ENSP00000408411.2
	LAMP2	ENST00000371335.4	TSL:1	c.581C>T	p.Thr194Ile	missense	Exon 5 of 9	ENSP00000360386.4

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 23

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Cardiovascular phenotype (1)
-	1	-	Danon disease (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.092
CardioboostCm	Benign	0.0038
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.63
CADD	Benign	8.2
DANN	Uncertain	0.99
DEOGEN2	Benign	0.35	T
FATHMM_MKL	Benign	0.043	N
LIST_S2	Benign	0.72	T
M_CAP	Pathogenic	0.35	D
MetaRNN	Benign	0.27	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.6	M
PhyloP100		0.37
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-2.2	N
REVEL	Benign	0.062
Sift	Benign	0.032	D
Sift4G	Uncertain	0.032	D
Polyphen		0.73	P
Vest4		0.12
MutPred		0.66		Loss of disorder (P = 0.0308)
MVP		0.55
MPC		0.56
ClinPred		0.28	T
GERP RS		0.77
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.12
gMVP		0.64
Mutation Taster		=96/4	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs1033442580; hg19: chrX-119581856;