rs876657845

chrX-120447972-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM1 PM2 BP4_Moderate

The NM_002294.3(LAMP2):c.610A>C(p.Thr204Pro) 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. 14/21 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. T204I) has been classified 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: 0.669

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 2 ACMG points.

• PM1: In a glycosylation_site O-linked (GalNAc...) threonine (size 0) in uniprot entity LAMP2_HUMAN
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.16236565).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LAMP2	NM_002294.3	c.610A>C	p.Thr204Pro	missense_variant	5/9	ENST00000200639.9
LAMP2	NM_001122606.1	c.610A>C	p.Thr204Pro	missense_variant	5/9
LAMP2	NM_013995.2	c.610A>C	p.Thr204Pro	missense_variant	5/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LAMP2	ENST00000200639.9	c.610A>C	p.Thr204Pro	missense_variant	5/9	1	NM_002294.3	P3

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

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jul 16, 2015

The p.Thr204Pro variant in LAMP2 has not been previously reported in individuals with cardiomyopathy or in large population studies. While computational predict ion tools and conservation analysis do not provide strong support for or against an impact to the protein, pathogenic missense variants in LAMP2 are exceedingly rare (nearly all the disease-causing variants cause a truncated or absent prote in). In summary, the clinical significance of the p.Thr204Pro variant is uncerta in. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.080
CardioboostCm	Benign	0.0027
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.59
Cadd	Benign	16
Dann	Uncertain	0.99
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Benign	0.59	T;T;T
M_CAP	Benign	0.021	T
MetaRNN	Benign	0.16	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.9	L;L;L
MutationTaster	Benign	0.95	N;N;N;N;N
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-1.7	N;N;N
REVEL	Benign	0.083
Sift	Benign	0.22	T;T;T
Sift4G	Benign	0.10	T;T;T
Polyphen		0.053, 0.019	.;B;B
Vest4		0.20
MutPred		0.35		Loss of glycosylation at T204 (P = 0.0143);Loss of glycosylation at T204 (P = 0.0143);Loss of glycosylation at T204 (P = 0.0143);
MVP		0.62
MPC		0.39
ClinPred		0.38	T
GERP RS		3.0
Varity_R		0.38
gMVP		0.82

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

Publications

LitVar

Other links and lift over

dbSNP: rs876657845; hg19: chrX-119581827;