NM_002294.3:c.472A>G

Variant names:

• chrX-120449054-T-C
• rs138374063
• NM_002294.3:c.472A>G

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4_Moderate BP6 BS2

The NM_002294.3(LAMP2):​c.472A>G​(p.Thr158Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000274 in 1,203,455 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 10 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.000027 (0 hom., 0 hem., cov: 24)
  • Exomes 𝑓: 0.000027 (0 hom. 10 hem.)
• Consequence: LAMP2 NM_002294.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:3
• Conservation: PhyloP100: -0.131
• 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: Benign. The variant received -7 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.09538525).
• BP6: Variant X-120449054-T-C is Benign according to our data. Variant chrX-120449054-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 44429.
• BS2: High Hemizygotes in GnomAdExome4 at 10 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.472A>G	p.Thr158Ala	missense	Exon 4 of 9	NP_002285.1	P13473-1
	LAMP2	NM_001122606.1		c.472A>G	p.Thr158Ala	missense	Exon 4 of 9	NP_001116078.1	P13473-3
	LAMP2	NM_013995.2		c.472A>G	p.Thr158Ala	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.472A>G	p.Thr158Ala	missense	Exon 4 of 9	ENSP00000200639.4	P13473-1
	LAMP2	ENST00000434600.6	TSL:1	c.472A>G	p.Thr158Ala	missense	Exon 4 of 9	ENSP00000408411.2	P13473-3
	LAMP2	ENST00000371335.4	TSL:1	c.472A>G	p.Thr158Ala	missense	Exon 4 of 9	ENSP00000360386.4	P13473-2

Frequencies

GnomAD3 genomes AF: 0.0000267 AC: 3 AN: 112327 Hom.: 0 Cov.: 24

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: 0.0000375

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000328 AC: 6 AN: 183029 AF XY: 0.0000296

Gnomad AFR exome AF: 0.0000760

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000625

Gnomad NFE exome AF: 0.0000490

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000275 AC: 30 AN: 1091128 Hom.: 0 Cov.: 28 AF XY: 0.0000280 AC XY: 10 AN XY: 356618

African (AFR) AF: 0.00 AC: 0 AN: 26279

American (AMR) AF: 0.00 AC: 0 AN: 35187

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19342

East Asian (EAS) AF: 0.00 AC: 0 AN: 30159

South Asian (SAS) AF: 0.00 AC: 0 AN: 53937

European-Finnish (FIN) AF: 0.0000740 AC: 3 AN: 40529

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4108

European-Non Finnish (NFE) AF: 0.0000323 AC: 27 AN: 835713

Other (OTH) AF: 0.00 AC: 0 AN: 45874

GnomAD4 genome AF: 0.0000267 AC: 3 AN: 112327 Hom.: 0 Cov.: 24 AF XY: 0.00 AC XY: 0 AN XY: 34503

African (AFR) AF: 0.0000324 AC: 1 AN: 30908

American (AMR) AF: 0.00 AC: 0 AN: 10582

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2647

East Asian (EAS) AF: 0.00 AC: 0 AN: 3617

South Asian (SAS) AF: 0.00 AC: 0 AN: 2764

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6099

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

European-Non Finnish (NFE) AF: 0.0000375 AC: 2 AN: 53269

Other (OTH) AF: 0.00 AC: 0 AN: 1519

Alfa AF: 0.0000510 Hom.: 2

Bravo AF: 0.0000113

ESP6500AA AF: 0.000261 AC: 1

ESP6500EA AF: 0.000297 AC: 2

ExAC AF: 0.0000247 AC: 3

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.078
CardioboostCm	Benign	0.0048
BayesDel_addAF	Benign	-0.50	T
BayesDel_noAF	Benign	-0.77
CADD	Benign	8.4
DANN	Benign	0.80
DEOGEN2	Benign	0.31	T
FATHMM_MKL	Benign	0.066	N
LIST_S2	Benign	0.58	T
M_CAP	Benign	0.019	T
MetaRNN	Benign	0.095	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	1.9	L
PhyloP100		-0.13
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.073
Sift	Benign	0.25	T
Sift4G	Benign	0.17	T
Polyphen		0.0060	B
Vest4		0.062
MVP		0.57
MPC		0.27
ClinPred		0.022	T
GERP RS		-4.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.10
gMVP		0.43
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs138374063; hg19: chrX-119582909;