X-120469147-G-C

Variant names:

• chrX-120469147-G-C
• rs878854484
• NM_002294.3:c.23C>G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_002294.3(LAMP2):​c.23C>G​(p.Pro8Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 12/21 in silico tools predict a benign 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: 0.515

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.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LAMP2	NM_002294.3	c.23C>G	p.Pro8Arg	missense_variant	Exon 1 of 9	ENST00000200639.9	NP_002285.1
LAMP2	NM_001122606.1	c.23C>G	p.Pro8Arg	missense_variant	Exon 1 of 9		NP_001116078.1
LAMP2	NM_013995.2	c.23C>G	p.Pro8Arg	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.23C>G	p.Pro8Arg	missense_variant	Exon 1 of 9	1	NM_002294.3	ENSP00000200639.4
LAMP2	ENST00000434600.6	c.23C>G	p.Pro8Arg	missense_variant	Exon 1 of 9	1		ENSP00000408411.2
LAMP2	ENST00000371335.4	c.23C>G	p.Pro8Arg	missense_variant	Exon 1 of 9	1		ENSP00000360386.4
LAMP2	ENST00000706600.1	c.23C>G	p.Pro8Arg	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 provided Uncertain:1

Oct 31, 2017

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

A variant of uncertain significance has been identified in the LAMP2 gene. The P8R variant has not been published as pathogenic or been reported as benign to our knowledge. The P8R variant is not observed in large population cohorts (Lek et al., 2016). The P8R variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. However, this substitution occurs at a position not conserved across species and in silico analysis predicts this variant likely does not alter the protein structure/function. Lastly, a different missense change affecting the same residue (P8L) has been reported previously at GeneDx; however, the clinical significance of this variant is unknown. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.086
CardioboostCm	Benign	0.024
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.61
CADD	Benign	15
DANN	Uncertain	0.99
DEOGEN2	Benign	0.38	.;T;.
FATHMM_MKL	Benign	0.15	N
LIST_S2	Benign	0.74	T;T;T
M_CAP	Benign	0.017	T
MetaRNN	Uncertain	0.48	T;T;T
MetaSVM	Benign	-0.90	T
MutationAssessor	Uncertain	2.2	M;M;M
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-1.4	N;N;N
REVEL	Benign	0.12
Sift	Benign	0.052	T;D;T
Sift4G	Benign	0.061	T;T;T
Polyphen		1.0	.;D;D
Vest4		0.45
MutPred		0.65		Gain of MoRF binding (P = 0.0052);Gain of MoRF binding (P = 0.0052);Gain of MoRF binding (P = 0.0052);
MVP		0.56
MPC		0.82
ClinPred		0.75	D
GERP RS		0.090
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.053
gMVP		0.70

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: rs878854484; hg19: chrX-119603002;