X-120446414-A-G

Position:

• chrX-120446414-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The ENST00000200639.9(LAMP2):​c.755T>C​(p.Ile252Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00000182 in 1,096,844 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a pathogenic 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. I252S) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 22)
  • Exomes 𝑓: 0.0000018 (0 hom. 1 hem.)
• Consequence: LAMP2 ENST00000200639.9 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 4.15

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 Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.77

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LAMP2	NM_002294.3	c.755T>C	p.Ile252Thr	missense_variant	6/9	ENST00000200639.9	NP_002285.1
LAMP2	NM_001122606.1	c.755T>C	p.Ile252Thr	missense_variant	6/9		NP_001116078.1
LAMP2	NM_013995.2	c.755T>C	p.Ile252Thr	missense_variant	6/9		NP_054701.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LAMP2	ENST00000200639.9	c.755T>C	p.Ile252Thr	missense_variant	6/9	1	NM_002294.3	ENSP00000200639	P3

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD3 exomes AF: 0.00000545 AC: 1 AN: 183379 Hom.: 0 AF XY: 0.0000147 AC XY: 1 AN XY: 67835

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: 0.00

Gnomad OTH exome AF: 0.000221

GnomAD4 exome AF: 0.00000182 AC: 2 AN: 1096844 Hom.: 0 Cov.: 30 AF XY: 0.00000276 AC XY: 1 AN XY: 362244

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000568

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: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

May 22, 2023

- -

Danon disease Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jul 26, 2021

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has not been reported in the literature in individuals with LAMP2-related conditions. This variant is not present in population databases (ExAC no frequency). This sequence change replaces isoleucine with threonine at codon 252 of the LAMP2 protein (p.Ile252Thr). The isoleucine residue is weakly conserved and there is a moderate physicochemical difference between isoleucine and threonine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.37
CardioboostCm	Benign	0.0037
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.45
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.33	.;T;.
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.87	D;D;D
M_CAP	Benign	0.040	D
MetaRNN	Pathogenic	0.77	D;D;D
MetaSVM	Benign	-0.90	T
MutationAssessor	Uncertain	2.7	M;M;M
MutationTaster	Benign	0.94	N;N;N;N;N
PrimateAI	Uncertain	0.67	T
PROVEAN	Uncertain	-3.2	D;D;D
REVEL	Benign	0.18
Sift	Uncertain	0.0090	D;D;D
Sift4G	Uncertain	0.021	D;D;D
Polyphen		0.79, 0.85	.;P;P
Vest4		0.55
MutPred		0.82		Gain of disorder (P = 0.0216);Gain of disorder (P = 0.0216);Gain of disorder (P = 0.0216);
MVP		0.67
MPC		0.35
ClinPred		0.80	D
GERP RS		4.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.34
gMVP		0.72

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs141541387; hg19: chrX-119580269;