rs73219144

chrX-120442600-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_002294.3(LAMP2):c.927C>T(p.Ser309=) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0342 in 1,203,141 control chromosomes in the GnomAD database, including 591 homozygotes. There are 13,128 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.027 ( 39 hom., 838 hem., cov: 22)

Exomes 𝑓: 0.035 ( 552 hom. 12290 hem. )

Consequence

LAMP2
NM_002294.3 splice_region, synonymous

Scores

Splicing: ADA: 0.0004918

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:16

Conservation

PhyloP100: 0.349

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.52).

BP6

Variant X-120442600-G-A is Benign according to our data. Variant chrX-120442600-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 44445.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-120442600-G-A is described in Lovd as [Likely_benign]. Variant chrX-120442600-G-A is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=0.349 with no splicing effect.

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0267 (2983/111660) while in subpopulation NFE AF= 0.0408 (2166/53069). AF 95% confidence interval is 0.0394. There are 39 homozygotes in gnomad4. There are 838 alleles in male gnomad4 subpopulation. This position pass quality control queck.

BS2

High Homozygotes in GnomAd at 39 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
LAMP2	NM_002294.3 linkuse as main transcript	c.927C>T	p.Ser309=	splice_region_variant, synonymous_variant	7/9	ENST00000200639.9
LAMP2	NM_001122606.1 linkuse as main transcript	c.927C>T	p.Ser309=	splice_region_variant, synonymous_variant	7/9
LAMP2	NM_013995.2 linkuse as main transcript	c.927C>T	p.Ser309=	splice_region_variant, synonymous_variant	7/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LAMP2	ENST00000200639.9 linkuse as main transcript	c.927C>T	p.Ser309=	splice_region_variant, synonymous_variant	7/9	1	NM_002294.3	P3	P13473-1

Frequencies

GnomAD3 genomes

AF:

0.0268

AC:

2986

AN:

111606

Hom.:

Cov.:

AF XY:

0.0248

AC XY:

839

AN XY:

33806

show subpopulations

Gnomad AFR

AF:

0.00533

Gnomad AMI

AF:

0.0219

Gnomad AMR

AF:

0.0254

Gnomad ASJ

AF:

0.0284

Gnomad EAS

AF:

0.000280

Gnomad SAS

AF:

0.00859

Gnomad FIN

AF:

0.0383

Gnomad MID

AF:

0.0336

Gnomad NFE

AF:

0.0408

Gnomad OTH

AF:

0.0258

GnomAD3 exomes

AF:

0.0270

AC:

4943

AN:

183267

Hom.:

AF XY:

0.0282

AC XY:

1911

AN XY:

67737

show subpopulations

Gnomad AFR exome

AF:

0.00456

Gnomad AMR exome

AF:

0.0160

Gnomad ASJ exome

AF:

0.0297

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00828

Gnomad FIN exome

AF:

0.0389

Gnomad NFE exome

AF:

0.0400

Gnomad OTH exome

AF:

0.0385

GnomAD4 exome

AF:

0.0349

AC:

38118

AN:

1091481

Hom.:

552

Cov.:

AF XY:

0.0344

AC XY:

12290

AN XY:

357533

show subpopulations

Gnomad4 AFR exome

AF:

0.00361

Gnomad4 AMR exome

AF:

0.0163

Gnomad4 ASJ exome

AF:

0.0304

Gnomad4 EAS exome

AF:

0.0000331

Gnomad4 SAS exome

AF:

0.00922

Gnomad4 FIN exome

AF:

0.0394

Gnomad4 NFE exome

AF:

0.0396

Gnomad4 OTH exome

AF:

0.0326

GnomAD4 genome

AF:

0.0267

AC:

2983

AN:

111660

Hom.:

Cov.:

AF XY:

0.0247

AC XY:

838

AN XY:

33870

show subpopulations

Gnomad4 AFR

AF:

0.00532

Gnomad4 AMR

AF:

0.0254

Gnomad4 ASJ

AF:

0.0284

Gnomad4 EAS

AF:

0.000281

Gnomad4 SAS

AF:

0.00824

Gnomad4 FIN

AF:

0.0383

Gnomad4 NFE

AF:

0.0408

Gnomad4 OTH

AF:

0.0255

Alfa

AF:

0.0369

Hom.:

1644

Bravo

AF:

0.0246

EpiCase

AF:

0.0439

EpiControl

AF:

0.0395

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:16

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:7

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jun 09, 2011	This variant is classified as benign based on its high frequency in the general population (3%; LMM unpublished data). -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 07, 2016	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

Danon disease

Benign:4

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 22, 2023	- -
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	Invitae	Feb 01, 2024	- -
Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Oct 20, 2015	- -

Hypertrophic cardiomyopathy

Benign:2

Likely benign, no assertion criteria provided	clinical testing	Cohesion Phenomics	Sep 29, 2022	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -

Cardiovascular phenotype

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 20, 2015

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

-0.52

Cadd

Benign

5.4

Dann

Benign

0.62

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00049

dbscSNV1_RF

Benign

0.032

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over