rs140936359

chrX-120439252-T-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Moderate BP6_Very_Strong BS2

The ENST00000371335.4(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. 10/14 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 ENST00000371335.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 3.93

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]

ACMG classification

Verdict is Benign. Variant got -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 [Likely_benign]. Clinvar id is 180880.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Hemizygotes in GnomAd at 3 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LAMP2	NM_002294.3	c.1093+2478A>G		intron_variant		ENST00000200639.9
LAMP2	NM_013995.2	c.1135A>G	p.Ile379Val	missense_variant	9/9
LAMP2	NM_001122606.1	c.1093+2478A>G		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LAMP2	ENST00000200639.9	c.1093+2478A>G		intron_variant		1	NM_002294.3	P3

Frequencies

GnomAD3 genomes AF: 0.000134 AC: 15 AN: 111738 Hom.: 0 Cov.: 23 AF XY: 0.0000884 AC XY: 3 AN XY: 33918

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

GnomAD3 exomes AF: 0.0000873 AC: 16 AN: 183320 Hom.: 0 AF XY: 0.0000737 AC XY: 5 AN XY: 67822

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 SAS 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

Gnomad4 AFR exome AF: 0.0000379

Gnomad4 AMR exome AF: 0.0000284

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000494

Gnomad4 NFE exome AF: 0.000307

Gnomad4 OTH exome AF: 0.000543

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

Gnomad4 AFR AF: 0.0000325

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000263

Gnomad4 OTH AF: 0.00

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

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Danon disease Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Feb 02, 2022	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Likely benign. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with Danon disease (MIM#300257). (I) 0110 - This gene is associated with X-linked dominant disease. (I) 0115 - Variants in this gene are known to have variable expressivity. Phenotypic variability has been described, and males typically have earlier disease onset and more severe phenotypes than females (OMIM). (I) 0200 - Variant is predicted to result in a missense amino acid change from isoleucine to valine. (I) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD (v2) <0.001 for a dominant condition (12 heterozygotes, 0 homozygotes, 5 hemizygotes). (SP) 0503 - Missense variant consistently predicted to be tolerated by multiple in silico tools or not conserved in placental mammals with a minor amino acid change. (SB) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0808 - Previous reports of pathogenicity for this variant are conflicting. This variant has been reported as VUS and benign in ClinVar. It has also been reported as VUS in an individual with atrial fibrillation who also has a pathogenic KCNQ1 variant (PMID:31638414) and an individual with HCM who also has a likely pathogenic MYH7 variant (VCGS). (I) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -
Benign, criteria provided, single submitter	clinical testing	Invitae	Aug 08, 2021	- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Dec 11, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
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
MutationTaster	Benign	1.0	D;D;D;N;N
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

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

Publications

LitVar

Other links and lift over

dbSNP: rs140936359; hg19: chrX-119573107;