rs141541387

Variant names:

• chrX-120446414-A-C
• rs141541387
• NM_002294.3:c.755T>G

Your query was ambiguous. Multiple possible variants found:

• chrX-120446414-A-C
• chrX-120446414-A-G

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Moderate BP6_Very_Strong BS2

The NM_002294.3(LAMP2):​c.755T>G​(p.Ile252Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00181 in 1,208,328 control chromosomes in the GnomAD database, including 2 homozygotes. There are 695 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I252T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0012 (0 hom., 30 hem., cov: 22)
  • Exomes 𝑓: 0.0019 (2 hom. 665 hem.)
• Consequence: LAMP2 NM_002294.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:15
• Conservation: PhyloP100: 4.15
• Publications: 7 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.09243721).
• BP6: Variant X-120446414-A-C is Benign according to our data. Variant chrX-120446414-A-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 44437.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Hemizygotes in GnomAd4 at 30 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.755T>G	p.Ile252Ser	missense	Exon 6 of 9	NP_002285.1	P13473-1
	LAMP2	NM_001122606.1		c.755T>G	p.Ile252Ser	missense	Exon 6 of 9	NP_001116078.1	P13473-3
	LAMP2	NM_013995.2		c.755T>G	p.Ile252Ser	missense	Exon 6 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.755T>G	p.Ile252Ser	missense	Exon 6 of 9	ENSP00000200639.4	P13473-1
	LAMP2	ENST00000434600.6	TSL:1	c.755T>G	p.Ile252Ser	missense	Exon 6 of 9	ENSP00000408411.2	P13473-3
	LAMP2	ENST00000371335.4	TSL:1	c.755T>G	p.Ile252Ser	missense	Exon 6 of 9	ENSP00000360386.4	P13473-2

Frequencies

GnomAD3 genomes AF: 0.00117 AC: 130 AN: 111435 Hom.: 0 Cov.: 22

Gnomad AFR AF: 0.000360

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00115

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000167

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00196

Gnomad OTH AF: 0.00133

GnomAD2 exomes AF: 0.00105 AC: 193 AN: 183379 AF XY: 0.00114

Gnomad AFR exome AF: 0.000228

Gnomad AMR exome AF: 0.00102

Gnomad ASJ exome AF: 0.000134

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000125

Gnomad NFE exome AF: 0.00188

Gnomad OTH exome AF: 0.00110

GnomAD4 exome AF: 0.00188 AC: 2058 AN: 1096838 Hom.: 2 Cov.: 30 AF XY: 0.00184 AC XY: 665 AN XY: 362244

African (AFR) AF: 0.000341 AC: 9 AN: 26384

American (AMR) AF: 0.000994 AC: 35 AN: 35205

Ashkenazi Jewish (ASJ) AF: 0.000103 AC: 2 AN: 19370

East Asian (EAS) AF: 0.00 AC: 0 AN: 30192

South Asian (SAS) AF: 0.00 AC: 0 AN: 54114

European-Finnish (FIN) AF: 0.0000987 AC: 4 AN: 40518

Middle Eastern (MID) AF: 0.00169 AC: 7 AN: 4134

European-Non Finnish (NFE) AF: 0.00230 AC: 1930 AN: 840866

Other (OTH) AF: 0.00154 AC: 71 AN: 46055

GnomAD4 genome AF: 0.00117 AC: 130 AN: 111490 Hom.: 0 Cov.: 22 AF XY: 0.000891 AC XY: 30 AN XY: 33658

African (AFR) AF: 0.000359 AC: 11 AN: 30619

American (AMR) AF: 0.00114 AC: 12 AN: 10481

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2641

East Asian (EAS) AF: 0.00 AC: 0 AN: 3578

South Asian (SAS) AF: 0.00 AC: 0 AN: 2672

European-Finnish (FIN) AF: 0.000167 AC: 1 AN: 5980

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 218

European-Non Finnish (NFE) AF: 0.00196 AC: 104 AN: 53093

Other (OTH) AF: 0.00131 AC: 2 AN: 1521

Alfa AF: 0.00192 Hom.: 100

Bravo AF: 0.00127

TwinsUK AF: 0.00135 AC: 5

ALSPAC AF: 0.000692 AC: 2

ESP6500AA AF: 0.000261 AC: 1

ESP6500EA AF: 0.00253 AC: 17

ExAC AF: 0.00107 AC: 130

EpiCase AF: 0.00234

EpiControl AF: 0.00237

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	7	not specified (7)
-	-	4	Danon disease (4)
-	-	2	not provided (2)
-	-	1	Cardiomyopathy (1)
-	-	1	Cardiovascular phenotype (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.46
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.36
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Benign	0.32	T
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.88	D
M_CAP	Benign	0.052	D
MetaRNN	Benign	0.092	T
MetaSVM	Benign	-0.86	T
MutationAssessor	Uncertain	2.7	M
PhyloP100		4.1
PrimateAI	Uncertain	0.61	T
PROVEAN	Uncertain	-3.8	D
REVEL	Benign	0.17
Sift	Uncertain	0.0040	D
Sift4G	Uncertain	0.0090	D
Polyphen		0.65	P
Vest4		0.59
MVP		0.76
MPC		0.52
ClinPred		0.051	T
GERP RS		4.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.75
gMVP		0.89
Mutation Taster		=100/0	polymorphism (auto)

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: rs141541387; hg19: chrX-119580269;