rs145169006

Variant names:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_002294.3(LAMP2):c.661G>A(p.Gly221Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00221 in 1,209,052 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 848 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).

Frequency

Genomes: 𝑓 0.0019 ( 0 hom., 62 hem., cov: 23)

Exomes 𝑓: 0.0022 ( 0 hom. 786 hem. )

Consequence

LAMP2
NM_002294.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:18

Conservation

PhyloP100: 3.07

Publications

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

LAMP2 links:

Genome browser will be placed here

new If you want to explore the variant's impact on the transcript NM_002294.3, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.02191636).

BP6

Variant X-120447921-C-T is Benign according to our data. Variant chrX-120447921-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 44434.

BS2

High Hemizygotes in GnomAd4 at 62 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.661G>A	p.Gly221Arg	missense	Exon 5 of 9	NP_002285.1	P13473-1
LAMP2	NM_001122606.1		c.661G>A	p.Gly221Arg	missense	Exon 5 of 9	NP_001116078.1	P13473-3
LAMP2	NM_013995.2		c.661G>A	p.Gly221Arg	missense	Exon 5 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.661G>A	p.Gly221Arg	missense	Exon 5 of 9	ENSP00000200639.4	P13473-1
LAMP2	ENST00000434600.6	TSL:1	c.661G>A	p.Gly221Arg	missense	Exon 5 of 9	ENSP00000408411.2	P13473-3
LAMP2	ENST00000371335.4	TSL:1	c.661G>A	p.Gly221Arg	missense	Exon 5 of 9	ENSP00000360386.4	P13473-2

Frequencies

GnomAD3 genomes

AF:

0.00188

AC:

210

AN:

111755

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000390

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00495

Gnomad ASJ

AF:

0.00453

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000999

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00231

Gnomad OTH

AF:

0.00334

GnomAD2 exomes

AF:

0.00155

AC:

285

AN:

183483

AF XY:

0.00131

show subpopulations

Gnomad AFR exome

AF:

0.000608

Gnomad AMR exome

AF:

0.00175

Gnomad ASJ exome

AF:

0.00267

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00137

Gnomad NFE exome

AF:

0.00208

Gnomad OTH exome

AF:

0.00375

GnomAD4 exome

AF:

0.00224

AC:

2463

AN:

1097247

Hom.:

Cov.:

AF XY:

0.00217

AC XY:

786

AN XY:

362617

show subpopulations

African (AFR)

AF:

0.000152

AC:

AN:

26385

American (AMR)

AF:

0.00230

AC:

AN:

35203

Ashkenazi Jewish (ASJ)

AF:

0.00268

AC:

AN:

19374

East Asian (EAS)

AF:

0.00

AC:

AN:

30199

South Asian (SAS)

AF:

0.0000185

AC:

AN:

54123

European-Finnish (FIN)

AF:

0.00118

AC:

AN:

40532

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4133

European-Non Finnish (NFE)

AF:

0.00261

AC:

2194

AN:

841230

Other (OTH)

AF:

0.00180

AC:

AN:

46068

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.460

Heterozygous variant carriers

174

261

348

435

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

164

246

328

410

<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:

0.00188

AC:

210

AN:

111805

Hom.:

Cov.:

AF XY:

0.00182

AC XY:

AN XY:

33975

show subpopulations

African (AFR)

AF:

0.000389

AC:

AN:

30824

American (AMR)

AF:

0.00494

AC:

AN:

10518

Ashkenazi Jewish (ASJ)

AF:

0.00453

AC:

AN:

2648

East Asian (EAS)

AF:

0.00

AC:

AN:

3551

South Asian (SAS)

AF:

0.00

AC:

AN:

2696

European-Finnish (FIN)

AF:

0.000999

AC:

AN:

6004

Middle Eastern (MID)

AF:

0.00

AC:

AN:

218

European-Non Finnish (NFE)

AF:

0.00231

AC:

123

AN:

53142

Other (OTH)

AF:

0.00330

AC:

AN:

1516

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

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:

0.00236

Hom.:

110

Bravo

AF:

0.00214

EpiCase

AF:

0.00169

EpiControl

AF:

0.00237

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (6)

Danon disease (5)

not provided (4)

Cardiomyopathy (2)

Cardiovascular phenotype (1)

Intellectual disability (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.66

BayesDel_addAF

Benign

-0.26

BayesDel_noAF

Benign

-0.15

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.49

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.90

M_CAP

Pathogenic

0.88

MetaRNN

Benign

0.022

MetaSVM

Uncertain

-0.24

MutationAssessor

Pathogenic

3.2

PhyloP100

3.1

PrimateAI

Uncertain

0.49

PROVEAN

Pathogenic

-5.4

REVEL

Uncertain

0.41

Sift

Pathogenic

0.0

Sift4G

Uncertain

0.0030

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.74

gMVP

0.89

Mutation Taster

=97/3

polymorphism (auto)

(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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

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