rs140936359

Variant names:

• chrX-120439252-T-C
• rs140936359
• ENST00000371335.4:c.1135A>G

Variant summary

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

The NM_013995.2(LAMP2):​c.1135A>G​(p.Ile379Val) variant causes a missense change. The variant allele was found at a frequency of 0.00025 in 1,208,250 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 79 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 12/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00013 (0 hom., 3 hem., cov: 23)
  • Exomes 𝑓: 0.00026 (0 hom. 76 hem.)
• Consequence: LAMP2 NM_013995.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 3.93
• 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.116473705).
• BP6: Variant X-120439252-T-C is Benign according to our data. Variant chrX-120439252-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 180880.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Hemizygotes in GnomAd4 at 3 XL gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_013995.2. 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.1093+2478A>G		intron	N/A	NP_002285.1	P13473-1
	LAMP2	NM_013995.2		c.1135A>G	p.Ile379Val	missense	Exon 9 of 9	NP_054701.1	P13473-2
	LAMP2	NM_001122606.1		c.1093+2478A>G		intron	N/A	NP_001116078.1	P13473-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LAMP2	ENST00000371335.4	TSL:1	c.1135A>G	p.Ile379Val	missense	Exon 9 of 9	ENSP00000360386.4	P13473-2
	LAMP2	ENST00000200639.9	TSL:1 MANE Select	c.1093+2478A>G		intron	N/A	ENSP00000200639.4	P13473-1
	LAMP2	ENST00000434600.6	TSL:1	c.1093+2478A>G		intron	N/A	ENSP00000408411.2	P13473-3

Frequencies

GnomAD3 genomes AF: 0.000134 AC: 15 AN: 111738 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.0000325

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: 0.000263

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000873 AC: 16 AN: 183320 AF XY: 0.0000737

Gnomad AFR exome AF: 0.000152

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000159

Gnomad OTH exome AF: 0.000221

GnomAD4 exome AF: 0.000262 AC: 287 AN: 1096512 Hom.: 0 Cov.: 28 AF XY: 0.000210 AC XY: 76 AN XY: 361956

African (AFR) AF: 0.0000379 AC: 1 AN: 26366

American (AMR) AF: 0.0000284 AC: 1 AN: 35202

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19359

East Asian (EAS) AF: 0.00 AC: 0 AN: 30164

South Asian (SAS) AF: 0.00 AC: 0 AN: 54103

European-Finnish (FIN) AF: 0.0000494 AC: 2 AN: 40524

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4130

European-Non Finnish (NFE) AF: 0.000307 AC: 258 AN: 840632

Other (OTH) AF: 0.000543 AC: 25 AN: 46032

GnomAD4 genome AF: 0.000134 AC: 15 AN: 111738 Hom.: 0 Cov.: 23 AF XY: 0.0000884 AC XY: 3 AN XY: 33918

African (AFR) AF: 0.0000325 AC: 1 AN: 30734

American (AMR) AF: 0.00 AC: 0 AN: 10458

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2643

East Asian (EAS) AF: 0.00 AC: 0 AN: 3591

South Asian (SAS) AF: 0.00 AC: 0 AN: 2697

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6022

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 239

European-Non Finnish (NFE) AF: 0.000263 AC: 14 AN: 53171

Other (OTH) AF: 0.00 AC: 0 AN: 1498

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.0000718

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000346 AC: 1

ESP6500AA AF: 0.000261 AC: 1

ESP6500EA AF: 0.000149 AC: 1

ExAC AF: 0.0000824 AC: 10

EpiCase AF: 0.000545

EpiControl AF: 0.000119

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.085
BayesDel_addAF	Benign	-0.56	T
BayesDel_noAF	Benign	-0.78
CADD	Benign	20
DANN	Benign	0.96
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.58	T
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.12	T
MetaSVM	Benign	-1.0	T
PhyloP100		3.9
PROVEAN	Benign	-0.65	N
REVEL	Benign	0.046
Sift	Benign	0.17	T
Sift4G	Benign	0.22	T
Polyphen		0.0010	B
Vest4		0.35
MVP		0.56
ClinPred		0.11	T
GERP RS		2.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=88/12	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs140936359; hg19: chrX-119573107;