rs73219144

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_002294.3(LAMP2):c.927C>T(p.Ser309Ser) 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:18

Conservation

PhyloP100: 0.349

Publications

5 publications found

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 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

LAMP2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 Benign/Likely_benign. ClinVar VariationId is 44445.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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 the male GnomAd4 subpopulation. Median coverage is 22. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 39 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LAMP2	NM_002294.3 link	c.927C>T	p.Ser309Ser	splice_region_variant, synonymous_variant	Exon 7 of 9	ENST00000200639.9	NP_002285.1	P13473-1
LAMP2	NM_001122606.1 link	c.927C>T	p.Ser309Ser	splice_region_variant, synonymous_variant	Exon 7 of 9		NP_001116078.1	P13473-3
LAMP2	NM_013995.2 link	c.927C>T	p.Ser309Ser	splice_region_variant, synonymous_variant	Exon 7 of 9		NP_054701.1	P13473-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LAMP2	ENST00000200639.9 link	c.927C>T	p.Ser309Ser	splice_region_variant, synonymous_variant	Exon 7 of 9	1	NM_002294.3	ENSP00000200639.4		P13473-1

Frequencies

GnomAD3 genomes

AF:

0.0268

AC:

2986

AN:

111606

Hom.:

Cov.:

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

GnomAD2 exomes

AF:

0.0270

AC:

4943

AN:

183267

AF XY:

0.0282

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 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

African (AFR)

AF:

0.00361

AC:

AN:

26301

American (AMR)

AF:

0.0163

AC:

573

AN:

35198

Ashkenazi Jewish (ASJ)

AF:

0.0304

AC:

588

AN:

19343

East Asian (EAS)

AF:

0.0000331

AC:

AN:

30175

South Asian (SAS)

AF:

0.00922

AC:

498

AN:

54001

European-Finnish (FIN)

AF:

0.0394

AC:

1595

AN:

40443

Middle Eastern (MID)

AF:

0.0451

AC:

186

AN:

4127

European-Non Finnish (NFE)

AF:

0.0396

AC:

33085

AN:

836037

Other (OTH)

AF:

0.0326

AC:

1497

AN:

45856

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.464

Heterozygous variant carriers

1145

2289

3434

4578

5723

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1182

2364

3546

4728

5910

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0267

AC:

2983

AN:

111660

Hom.:

Cov.:

AF XY:

0.0247

AC XY:

838

AN XY:

33870

show subpopulations

African (AFR)

AF:

0.00532

AC:

164

AN:

30810

American (AMR)

AF:

0.0254

AC:

267

AN:

10525

Ashkenazi Jewish (ASJ)

AF:

0.0284

AC:

AN:

2639

East Asian (EAS)

AF:

0.000281

AC:

AN:

3560

South Asian (SAS)

AF:

0.00824

AC:

AN:

2671

European-Finnish (FIN)

AF:

0.0383

AC:

228

AN:

5957

Middle Eastern (MID)

AF:

0.0276

AC:

AN:

217

European-Non Finnish (NFE)

AF:

0.0408

AC:

2166

AN:

53069

Other (OTH)

AF:

0.0255

AC:

AN:

1528

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

Heterozygous variant carriers

108

217

325

434

542

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

120

150

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0346

Hom.:

1657

Bravo

AF:

0.0246

EpiCase

AF:

0.0439

EpiControl

AF:

0.0395

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:18

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:8

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jun 09, 2011

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is classified as benign based on its high frequency in the general population (3%; LMM unpublished data). -

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

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

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

- -

Jun 07, 2016

Eurofins Ntd Llc (ga)

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

- -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Danon disease

Benign:4

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Nov 01, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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. -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not provided

Benign:3

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

- -

Mar 03, 2015

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Hypertrophic cardiomyopathy

Benign:2

Sep 29, 2022

Cohesion Phenomics

Significance:Likely 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

Jul 20, 2015

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

-0.52

CADD

Benign

5.4

(source)

DANN

Benign

0.62

PhyloP100

0.35

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=63/37

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over