chrX-120456677-G-A

Variant names:

• chrX-120456677-G-A
• rs752321157
• NM_002294.3:c.157C>T

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.157C>T​(p.Arg53Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000129 in 1,145,050 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 39 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). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R53H) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000090 (0 hom., 2 hem., cov: 22)
  • Exomes 𝑓: 0.00013 (0 hom. 37 hem.)
• Consequence: LAMP2 NM_002294.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:6
• Conservation: PhyloP100: -0.540
• Publications: 3 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=0.12744626).
• BP6: Variant X-120456677-G-A is Benign according to our data. Variant chrX-120456677-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 367788.
• BS2: High Hemizygotes in GnomAd4 at 2 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.157C>T	p.Arg53Cys	missense	Exon 2 of 9	NP_002285.1	P13473-1
	LAMP2	NM_001122606.1		c.157C>T	p.Arg53Cys	missense	Exon 2 of 9	NP_001116078.1	P13473-3
	LAMP2	NM_013995.2		c.157C>T	p.Arg53Cys	missense	Exon 2 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.157C>T	p.Arg53Cys	missense	Exon 2 of 9	ENSP00000200639.4	P13473-1
	LAMP2	ENST00000434600.6	TSL:1	c.157C>T	p.Arg53Cys	missense	Exon 2 of 9	ENSP00000408411.2	P13473-3
	LAMP2	ENST00000371335.4	TSL:1	c.157C>T	p.Arg53Cys	missense	Exon 2 of 9	ENSP00000360386.4	P13473-2

Frequencies

GnomAD3 genomes AF: 0.0000898 AC: 10 AN: 111337 Hom.: 0 Cov.: 22

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000961

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000370

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000151

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000104 AC: 18 AN: 173195 AF XY: 0.000102

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000381

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000156

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000133 AC: 138 AN: 1033713 Hom.: 0 Cov.: 19 AF XY: 0.000116 AC XY: 37 AN XY: 317759

African (AFR) AF: 0.0000397 AC: 1 AN: 25188

American (AMR) AF: 0.0000579 AC: 2 AN: 34561

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18832

East Asian (EAS) AF: 0.00 AC: 0 AN: 29760

South Asian (SAS) AF: 0.000278 AC: 14 AN: 50321

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 39939

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2957

European-Non Finnish (NFE) AF: 0.000150 AC: 118 AN: 788337

Other (OTH) AF: 0.0000685 AC: 3 AN: 43818

GnomAD4 genome AF: 0.0000898 AC: 10 AN: 111337 Hom.: 0 Cov.: 22 AF XY: 0.0000596 AC XY: 2 AN XY: 33541

African (AFR) AF: 0.00 AC: 0 AN: 30640

American (AMR) AF: 0.0000961 AC: 1 AN: 10410

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2651

East Asian (EAS) AF: 0.00 AC: 0 AN: 3584

South Asian (SAS) AF: 0.000370 AC: 1 AN: 2702

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5856

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 236

European-Non Finnish (NFE) AF: 0.000151 AC: 8 AN: 53098

Other (OTH) AF: 0.00 AC: 0 AN: 1479

Alfa AF: 0.000217 Hom.: 1

Bravo AF: 0.000102

ExAC AF: 0.0000989 AC: 12

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	2	Danon disease (2)
-	-	2	not provided (2)
-	1	-	Hypertrophic cardiomyopathy (1)
-	-	1	LAMP2-related disorder (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
CardioboostCm	Benign	0.0039
BayesDel_addAF	Benign	-0.57	T
BayesDel_noAF	Benign	-0.76
CADD	Benign	13
DANN	Benign	0.93
DEOGEN2	Uncertain	0.48	T
FATHMM_MKL	Benign	0.016	N
LIST_S2	Benign	0.69	T
M_CAP	Benign	0.028	D
MetaRNN	Benign	0.13	T
MetaSVM	Benign	-0.80	T
MutationAssessor	Benign	1.4	L
PhyloP100		-0.54
PrimateAI	Benign	0.24	T
PROVEAN	Benign	-2.3	N
REVEL	Benign	0.12
Sift	Benign	0.052	T
Sift4G	Uncertain	0.052	T
Polyphen		0.93	P
Vest4		0.10
MVP		0.24
MPC		0.72
ClinPred		0.099	T
GERP RS		-8.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.11
gMVP		0.58
Mutation Taster		=97/3	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: rs752321157; hg19: chrX-119590532; COSMIC: COSV108744934;