chrX-120456678-T-A

Variant names:

• chrX-120456678-T-A
• rs12097
• NM_002294.3:c.156A>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_002294.3(LAMP2):​c.156A>T​(p.Val52Val) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.413 in 1,146,848 control chromosomes in the GnomAD database, including 69,015 homozygotes. There are 144,907 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. V52V) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.39 (6245 hom., 12724 hem., cov: 22)
  • Exomes 𝑓: 0.41 (62770 hom. 132183 hem.)
• Consequence: LAMP2 NM_002294.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:15
• Conservation: PhyloP100: 2.43
• Publications: 17 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: ClinGen, G2P, Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Orphanet

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant X-120456678-T-A is Benign according to our data. Variant chrX-120456678-T-A is described in ClinVar as [Likely_benign]. Clinvar id is 44416.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=2.43 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.423 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LAMP2	NM_002294.3	c.156A>T	p.Val52Val	synonymous_variant	Exon 2 of 9	ENST00000200639.9	NP_002285.1
LAMP2	NM_001122606.1	c.156A>T	p.Val52Val	synonymous_variant	Exon 2 of 9		NP_001116078.1
LAMP2	NM_013995.2	c.156A>T	p.Val52Val	synonymous_variant	Exon 2 of 9		NP_054701.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LAMP2	ENST00000200639.9	c.156A>T	p.Val52Val	synonymous_variant	Exon 2 of 9	1	NM_002294.3	ENSP00000200639.4
LAMP2	ENST00000434600.6	c.156A>T	p.Val52Val	synonymous_variant	Exon 2 of 9	1		ENSP00000408411.2
LAMP2	ENST00000371335.4	c.156A>T	p.Val52Val	synonymous_variant	Exon 2 of 9	1		ENSP00000360386.4
LAMP2	ENST00000706600.1	c.156A>T	p.Val52Val	synonymous_variant	Exon 2 of 9			ENSP00000516464.1

Frequencies

GnomAD3 genomes AF: 0.394 AC: 43545 AN: 110486 Hom.: 6253 Cov.: 22

Gnomad AFR AF: 0.348

Gnomad AMI AF: 0.613

Gnomad AMR AF: 0.316

Gnomad ASJ AF: 0.409

Gnomad EAS AF: 0.388

Gnomad SAS AF: 0.390

Gnomad FIN AF: 0.450

Gnomad MID AF: 0.485

Gnomad NFE AF: 0.427

Gnomad OTH AF: 0.374

GnomAD2 exomes AF: 0.390 AC: 66801 AN: 171407 AF XY: 0.379

Gnomad AFR exome AF: 0.339

Gnomad AMR exome AF: 0.311

Gnomad ASJ exome AF: 0.405

Gnomad EAS exome AF: 0.382

Gnomad FIN exome AF: 0.446

Gnomad NFE exome AF: 0.412

Gnomad OTH exome AF: 0.381

GnomAD4 exome AF: 0.415 AC: 429603 AN: 1036315 Hom.: 62770 Cov.: 19 AF XY: 0.410 AC XY: 132183 AN XY: 322115

African (AFR) AF: 0.343 AC: 8649 AN: 25201

American (AMR) AF: 0.316 AC: 10862 AN: 34395

Ashkenazi Jewish (ASJ) AF: 0.414 AC: 7807 AN: 18856

East Asian (EAS) AF: 0.392 AC: 11648 AN: 29724

South Asian (SAS) AF: 0.412 AC: 20842 AN: 50568

European-Finnish (FIN) AF: 0.454 AC: 18099 AN: 39878

Middle Eastern (MID) AF: 0.402 AC: 1197 AN: 2980

European-Non Finnish (NFE) AF: 0.420 AC: 332524 AN: 790906

Other (OTH) AF: 0.410 AC: 17975 AN: 43807

GnomAD4 genome AF: 0.394 AC: 43558 AN: 110533 Hom.: 6245 Cov.: 22 AF XY: 0.388 AC XY: 12724 AN XY: 32819

African (AFR) AF: 0.348 AC: 10619 AN: 30486

American (AMR) AF: 0.315 AC: 3268 AN: 10373

Ashkenazi Jewish (ASJ) AF: 0.409 AC: 1079 AN: 2637

East Asian (EAS) AF: 0.388 AC: 1355 AN: 3496

South Asian (SAS) AF: 0.387 AC: 1028 AN: 2654

European-Finnish (FIN) AF: 0.450 AC: 2577 AN: 5730

Middle Eastern (MID) AF: 0.477 AC: 102 AN: 214

European-Non Finnish (NFE) AF: 0.427 AC: 22562 AN: 52782

Other (OTH) AF: 0.375 AC: 560 AN: 1495

Alfa AF: 0.416 Hom.: 4186

Bravo AF: 0.386

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:15

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:7

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Sep 25, 2012

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Apr 09, 2025

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 08, 2016

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 28, 2006

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Danon disease Benign:3

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Aug 19, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:2

Oct 20, 2015

Mayo Clinic Laboratories, Mayo Clinic

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Hypertrophic cardiomyopathy Benign:2

Oct 10, 2022

Cohesion Phenomics

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Cardiovascular phenotype Benign:1

Nov 24, 2014

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	6.0
DANN	Benign	0.45
PhyloP100		2.4
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: rs12097; hg19: chrX-119590533; COSMIC: COSV52354151;