NM_002294.3:c.520C>A

Variant names:

• chrX-120449006-G-T
• rs104894857
• NM_002294.3:c.520C>A

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.520C>A​(p.Gln174Lys) variant causes a missense change. The variant allele was found at a frequency of 0.00000166 in 1,207,951 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. Q174Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000089 (0 hom., 0 hem., cov: 23)
  • Exomes 𝑓: 9.1e-7 (0 hom. 0 hem.)
• Consequence: LAMP2 NM_002294.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 4.10
• Publications: 5 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: G2P, Labcorp Genetics (formerly Invitae), Orphanet, ClinGen, Genomics England PanelApp

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, 0.934

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002294.3. 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.520C>A	p.Gln174Lys	missense	Exon 4 of 9	NP_002285.1	P13473-1
	LAMP2	NM_001122606.1		c.520C>A	p.Gln174Lys	missense	Exon 4 of 9	NP_001116078.1	P13473-3
	LAMP2	NM_013995.2		c.520C>A	p.Gln174Lys	missense	Exon 4 of 9	NP_054701.1	P13473-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LAMP2	ENST00000200639.9	TSL:1 MANE Select	c.520C>A	p.Gln174Lys	missense	Exon 4 of 9	ENSP00000200639.4	P13473-1
	LAMP2	ENST00000434600.6	TSL:1	c.520C>A	p.Gln174Lys	missense	Exon 4 of 9	ENSP00000408411.2	P13473-3
	LAMP2	ENST00000371335.4	TSL:1	c.520C>A	p.Gln174Lys	missense	Exon 4 of 9	ENSP00000360386.4	P13473-2

Frequencies

GnomAD3 genomes AF: 0.00000893 AC: 1 AN: 111993 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.0000324

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 9.12e-7 AC: 1 AN: 1095958 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 361394

African (AFR) AF: 0.0000379 AC: 1 AN: 26366

American (AMR) AF: 0.00 AC: 0 AN: 35198

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19369

East Asian (EAS) AF: 0.00 AC: 0 AN: 30172

South Asian (SAS) AF: 0.00 AC: 0 AN: 54081

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40525

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4122

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 840103

Other (OTH) AF: 0.00 AC: 0 AN: 46022

GnomAD4 genome AF: 0.00000893 AC: 1 AN: 111993 Hom.: 0 Cov.: 23 AF XY: 0.00 AC XY: 0 AN XY: 34171

African (AFR) AF: 0.0000324 AC: 1 AN: 30850

American (AMR) AF: 0.00 AC: 0 AN: 10512

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2640

East Asian (EAS) AF: 0.00 AC: 0 AN: 3604

South Asian (SAS) AF: 0.00 AC: 0 AN: 2736

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5997

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 238

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 53229

Other (OTH) AF: 0.00 AC: 0 AN: 1505

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Cardiovascular phenotype (1)
-	1	-	Danon disease (1)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.61
CardioboostCm	Uncertain	0.53
BayesDel_addAF	Pathogenic	0.30	D
BayesDel_noAF	Pathogenic	0.20
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.42	T
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.88	D
M_CAP	Benign	0.052	D
MetaRNN	Pathogenic	0.93	D
MetaSVM	Benign	-0.44	T
MutationAssessor	Pathogenic	3.3	M
PhyloP100		4.1
PrimateAI	Benign	0.43	T
PROVEAN	Uncertain	-2.9	D
REVEL	Uncertain	0.46
Sift	Uncertain	0.0040	D
Sift4G	Uncertain	0.0090	D
Polyphen		0.99	D
Vest4		0.67
MutPred		0.85		Gain of methylation at Q174 (P = 0.0113)
MVP		0.90
MPC		1.0
ClinPred		0.99	D
GERP RS		5.5
Varity_R		0.86
gMVP		0.90
Mutation Taster		=70/30	polymorphism

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: rs104894857; hg19: chrX-119582861;