rs149276836

Variant names:

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4_ModerateBP6BS2

The NM_002294.3(LAMP2):c.385G>A(p.Ala129Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000929 in 1,194,244 control chromosomes in the GnomAD database, including 1 homozygotes. There are 26 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A129S) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00044 ( 0 hom., 10 hem., cov: 20)

Exomes 𝑓: 0.000057 ( 1 hom. 16 hem. )

Consequence

LAMP2
NM_002294.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:6

Conservation

PhyloP100: 3.53

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: G2P, Labcorp Genetics (formerly Invitae), Orphanet, ClinGen, Genomics England PanelApp

LAMP2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -7 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.10014692).

BP6

Variant X-120455369-C-T is Benign according to our data. Variant chrX-120455369-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 180871.

BS2

High Hemizygotes in GnomAd4 at 10 XL gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002294.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
LAMP2	NM_002294.3	MANE Select	c.385G>A	p.Ala129Thr	missense	Exon 3 of 9	NP_002285.1	P13473-1
LAMP2	NM_001122606.1		c.385G>A	p.Ala129Thr	missense	Exon 3 of 9	NP_001116078.1	P13473-3
LAMP2	NM_013995.2		c.385G>A	p.Ala129Thr	missense	Exon 3 of 9	NP_054701.1	P13473-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
LAMP2	ENST00000200639.9	TSL:1 MANE Select	c.385G>A	p.Ala129Thr	missense	Exon 3 of 9	ENSP00000200639.4	P13473-1
LAMP2	ENST00000434600.6	TSL:1	c.385G>A	p.Ala129Thr	missense	Exon 3 of 9	ENSP00000408411.2	P13473-3
LAMP2	ENST00000371335.4	TSL:1	c.385G>A	p.Ala129Thr	missense	Exon 3 of 9	ENSP00000360386.4	P13473-2

Frequencies

GnomAD3 genomes

AF:

0.000443

AC:

AN:

110519

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00142

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000585

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000125

AC:

AN:

183357

AF XY:

0.0000590

show subpopulations

Gnomad AFR exome

AF:

0.00152

Gnomad AMR exome

AF:

0.0000729

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000221

GnomAD4 exome

AF:

0.0000572

AC:

AN:

1083673

Hom.:

Cov.:

AF XY:

0.0000457

AC XY:

AN XY:

350303

show subpopulations

African (AFR)

AF:

0.00165

AC:

AN:

26137

American (AMR)

AF:

0.000227

AC:

AN:

35192

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19302

East Asian (EAS)

AF:

0.00

AC:

AN:

30144

South Asian (SAS)

AF:

0.0000372

AC:

AN:

53834

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40525

Middle Eastern (MID)

AF:

0.000244

AC:

AN:

4100

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

828817

Other (OTH)

AF:

0.000175

AC:

AN:

45622

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.456

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<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:

0.000443

AC:

AN:

110571

Hom.:

Cov.:

AF XY:

0.000305

AC XY:

AN XY:

32827

show subpopulations

African (AFR)

AF:

0.00141

AC:

AN:

30432

American (AMR)

AF:

0.000584

AC:

AN:

10272

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2637

East Asian (EAS)

AF:

0.00

AC:

AN:

3546

South Asian (SAS)

AF:

0.00

AC:

AN:

2601

European-Finnish (FIN)

AF:

0.00

AC:

AN:

5797

Middle Eastern (MID)

AF:

0.00

AC:

AN:

216

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

52887

Other (OTH)

AF:

0.00

AC:

AN:

1503

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.485

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<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:

0.000947

Hom.:

Bravo

AF:

0.000472

ESP6500AA

AF:

0.000782

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000132

AC:

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Cardiomyopathy (1)

Cardiovascular phenotype (1)

Danon disease (1)

LAMP2-related disorder (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.21

CardioboostCm

Uncertain

0.12

BayesDel_addAF

Benign

-0.33

BayesDel_noAF

Benign

-0.27

CADD

Uncertain

(source)

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.34

FATHMM_MKL

Uncertain

0.91

LIST_S2

Uncertain

0.89

M_CAP

Pathogenic

0.49

MetaRNN

Benign

0.10

MetaSVM

Benign

-0.45

MutationAssessor

Pathogenic

3.4

PhyloP100

3.5

PrimateAI

Benign

0.45

PROVEAN

Uncertain

-3.3

REVEL

Uncertain

0.34

Sift

Uncertain

0.0030

Sift4G

Uncertain

0.0070

Polyphen

1.0

Vest4

0.53

MVP

0.80

MPC

0.86

ClinPred

0.28

GERP RS

5.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.69

gMVP

0.74

Mutation Taster

=93/7

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over