rs3180515

Variant names:

• chrX-120469138-C-A
• rs3180515
• NM_002294.3:c.32G>T

Your query was ambiguous. Multiple possible variants found:

• chrX-120469138-C-A
• chrX-120469138-C-G

Variant summary

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

The NM_002294.3(LAMP2):​c.32G>T​(p.Gly11Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000729 in 1,098,126 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 3 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. G11S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.0000073 (0 hom. 3 hem.)
• Consequence: LAMP2 NM_002294.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:2
• Conservation: PhyloP100: 0.901
• Publications: 2 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-120469138-C-A is Benign according to our data. Variant chrX-120469138-C-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 163820.
• BS2: High Hemizygotes in GnomAdExome4 at 3 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.32G>T	p.Gly11Val	missense	Exon 1 of 9	NP_002285.1	P13473-1
	LAMP2	NM_001122606.1		c.32G>T	p.Gly11Val	missense	Exon 1 of 9	NP_001116078.1	P13473-3
	LAMP2	NM_013995.2		c.32G>T	p.Gly11Val	missense	Exon 1 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.32G>T	p.Gly11Val	missense	Exon 1 of 9	ENSP00000200639.4	P13473-1
	LAMP2	ENST00000434600.6	TSL:1	c.32G>T	p.Gly11Val	missense	Exon 1 of 9	ENSP00000408411.2	P13473-3
	LAMP2	ENST00000371335.4	TSL:1	c.32G>T	p.Gly11Val	missense	Exon 1 of 9	ENSP00000360386.4	P13473-2

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome AF: 0.00000729 AC: 8 AN: 1098126 Hom.: 0 Cov.: 30 AF XY: 0.00000825 AC XY: 3 AN XY: 363514

African (AFR) AF: 0.00 AC: 0 AN: 26398

American (AMR) AF: 0.00 AC: 0 AN: 35207

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19383

East Asian (EAS) AF: 0.00 AC: 0 AN: 30205

South Asian (SAS) AF: 0.00 AC: 0 AN: 54145

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40516

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4131

European-Non Finnish (NFE) AF: 0.00000950 AC: 8 AN: 842059

Other (OTH) AF: 0.00 AC: 0 AN: 46082

GnomAD4 genome Cov.: 23

Alfa AF: 0.0000358 Hom.: 0

Bravo AF: 0.0000189

EpiCase AF: 0.000109

EpiControl AF: 0.00

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	1	Danon disease (2)
-	2	-	not provided (2)
-	-	1	Cardiovascular phenotype (1)
-	1	-	Primary dilated cardiomyopathy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.081
CardioboostCm	Benign	0.036
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	19
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.66	D
FATHMM_MKL	Benign	0.31	N
LIST_S2	Benign	0.81	T
M_CAP	Uncertain	0.28	D
MetaRNN	Uncertain	0.61	D
MetaSVM	Benign	-0.65	T
MutationAssessor	Uncertain	2.2	M
PhyloP100		0.90
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-2.0	N
REVEL	Benign	0.22
Sift	Pathogenic	0.0	D
Sift4G	Benign	0.13	T
Polyphen		1.0	D
Vest4		0.43
MutPred		0.58		Gain of sheet (P = 0.0477)
MVP		0.64
MPC		0.95
ClinPred		0.93	D
GERP RS		4.1
PromoterAI		0.16	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.20
gMVP		0.55
Mutation Taster		=92/8	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: rs3180515; hg19: chrX-119602993;