rs139633545

Variant names:

• chrX-120431414-A-G
• rs139633545
• NM_002294.3:c.1142T>C

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP6 BS2

The NM_002294.3(LAMP2):​c.1142T>C​(p.Val381Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000546 in 1,209,735 control chromosomes in the GnomAD database, including 1 homozygotes. There are 21 hemizygotes in GnomAD. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V381L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00023 (0 hom., 7 hem., cov: 23)
  • Exomes 𝑓: 0.000036 (1 hom. 14 hem.)
• Consequence: LAMP2 NM_002294.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:5
• Conservation: PhyloP100: 8.51
• Publications: 4 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: Likely_benign. The variant received -5 ACMG points.

• BP6: Variant X-120431414-A-G is Benign according to our data. Variant chrX-120431414-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 180882.
• BS2: High Hemizygotes in GnomAd4 at 7 XL gene

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.1142T>C	p.Val381Ala	missense	Exon 9 of 9	NP_002285.1	P13473-1
	LAMP2	NM_001122606.1		c.1094-2788T>C		intron	N/A	NP_001116078.1	P13473-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LAMP2	ENST00000200639.9	TSL:1 MANE Select	c.1142T>C	p.Val381Ala	missense	Exon 9 of 9	ENSP00000200639.4	P13473-1
	LAMP2	ENST00000434600.6	TSL:1	c.1094-2788T>C		intron	N/A	ENSP00000408411.2	P13473-3
	LAMP2	ENST00000866856.1		c.1268T>C	p.Val423Ala	missense	Exon 10 of 10	ENSP00000536915.1

Frequencies

GnomAD3 genomes AF: 0.000232 AC: 26 AN: 112272 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.000711

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000555

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00133

GnomAD2 exomes AF: 0.000116 AC: 21 AN: 181255 AF XY: 0.000119

Gnomad AFR exome AF: 0.00106

Gnomad AMR exome AF: 0.0000730

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000361

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000364 AC: 40 AN: 1097463 Hom.: 1 Cov.: 29 AF XY: 0.0000386 AC XY: 14 AN XY: 362985

African (AFR) AF: 0.000265 AC: 7 AN: 26376

American (AMR) AF: 0.0000568 AC: 2 AN: 35202

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19354

East Asian (EAS) AF: 0.000132 AC: 4 AN: 30199

South Asian (SAS) AF: 0.00 AC: 0 AN: 54119

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

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4134

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 841485

Other (OTH) AF: 0.000586 AC: 27 AN: 46069

GnomAD4 genome AF: 0.000232 AC: 26 AN: 112272 Hom.: 0 Cov.: 23 AF XY: 0.000203 AC XY: 7 AN XY: 34446

African (AFR) AF: 0.000711 AC: 22 AN: 30946

American (AMR) AF: 0.00 AC: 0 AN: 10583

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2650

East Asian (EAS) AF: 0.000555 AC: 2 AN: 3606

South Asian (SAS) AF: 0.00 AC: 0 AN: 2718

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6104

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 53233

Other (OTH) AF: 0.00133 AC: 2 AN: 1507

Alfa AF: 0.000186 Hom.: 5

Bravo AF: 0.000253

ESP6500AA AF: 0.00156 AC: 6

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000165 AC: 20

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	1	-	Cardiomyopathy (1)
-	-	1	Cardiovascular phenotype (1)
-	-	1	Danon disease (1)
-	-	1	LAMP2-related disorder (1)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.52
CardioboostCm	Benign	0.062
BayesDel_addAF	Uncertain	0.081	D
BayesDel_noAF	Pathogenic	0.29
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.46	T
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.88	D
M_CAP	Pathogenic	0.44	D
MetaRNN	Uncertain	0.56	D
MetaSVM	Uncertain	-0.058	T
MutationAssessor	Pathogenic	3.1	M
PhyloP100		8.5
PROVEAN	Uncertain	-3.9	D
REVEL	Pathogenic	0.65
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.73
MVP		0.96
ClinPred		0.22	T
GERP RS		5.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.89
Mutation Taster		=81/19	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.14		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: rs139633545; hg19: chrX-119565269;