rs12097

Positions:

• chrX-120456678-T-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_002294.3(LAMP2):​c.156A>T​(p.Val52=) 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:13
• Conservation: PhyloP100: 2.43

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 -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. Variant chrX-120456678-T-A is described in Lovd as [Benign]. Variant chrX-120456678-T-A is described in Lovd as [Likely_benign].
• 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/exons	MANE	UniProt
LAMP2	NM_002294.3	c.156A>T	p.Val52=	synonymous_variant	2/9	ENST00000200639.9
LAMP2	NM_001122606.1	c.156A>T	p.Val52=	synonymous_variant	2/9
LAMP2	NM_013995.2	c.156A>T	p.Val52=	synonymous_variant	2/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LAMP2	ENST00000200639.9	c.156A>T	p.Val52=	synonymous_variant	2/9	1	NM_002294.3	P3
LAMP2	ENST00000434600.6	c.156A>T	p.Val52=	synonymous_variant	2/9	1		A1
LAMP2	ENST00000371335.4	c.156A>T	p.Val52=	synonymous_variant	2/9	1		A1
LAMP2	ENST00000706600.1	c.156A>T	p.Val52=	synonymous_variant	2/9

Frequencies

GnomAD3 genomes AF: 0.394 AC: 43545 AN: 110486 Hom.: 6253 Cov.: 22 AF XY: 0.387 AC XY: 12685 AN XY: 32760

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

GnomAD3 exomes AF: 0.390 AC: 66801 AN: 171407 Hom.: 9060 AF XY: 0.379 AC XY: 21867 AN XY: 57763

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 SAS exome AF: 0.400

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

Gnomad4 AFR exome AF: 0.343

Gnomad4 AMR exome AF: 0.316

Gnomad4 ASJ exome AF: 0.414

Gnomad4 EAS exome AF: 0.392

Gnomad4 SAS exome AF: 0.412

Gnomad4 FIN exome AF: 0.454

Gnomad4 NFE exome AF: 0.420

Gnomad4 OTH exome AF: 0.410

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

Gnomad4 AFR AF: 0.348

Gnomad4 AMR AF: 0.315

Gnomad4 ASJ AF: 0.409

Gnomad4 EAS AF: 0.388

Gnomad4 SAS AF: 0.387

Gnomad4 FIN AF: 0.450

Gnomad4 NFE AF: 0.427

Gnomad4 OTH AF: 0.375

Alfa AF: 0.416 Hom.: 4186

Bravo AF: 0.386

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:13

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:6

Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 25, 2012	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. -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Oct 28, 2006	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 08, 2016	- -

Danon disease Benign:3

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	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. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Aug 19, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

Hypertrophic cardiomyopathy Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -
Benign, no assertion criteria provided	clinical testing	Cohesion Phenomics	Oct 10, 2022	- -

not provided Benign:1

Benign, no assertion criteria provided

clinical testing

Mayo Clinic Laboratories, Mayo Clinic

Oct 20, 2015

- -

Cardiovascular phenotype Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 24, 2014

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

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

Publications

LitVar

Other links and lift over

dbSNP: rs12097; hg19: chrX-119590533; COSMIC: COSV52354151;