X-120456676-C-T

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.158G>A(p.Arg53His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000596 in 1,141,869 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 41 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict 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. R53C) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000063 ( 0 hom., 3 hem., cov: 22)

Exomes 𝑓: 0.000059 ( 0 hom. 38 hem. )

Consequence

LAMP2
NM_002294.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:2

Conservation

PhyloP100: -4.44

Publications

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

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=0.026464343).

BP6

Variant X-120456676-C-T is Benign according to our data. Variant chrX-120456676-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 44417.

BS2

High Hemizygotes in GnomAd4 at 3 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.158G>A	p.Arg53His	missense	Exon 2 of 9	NP_002285.1	P13473-1
LAMP2	NM_001122606.1		c.158G>A	p.Arg53His	missense	Exon 2 of 9	NP_001116078.1	P13473-3
LAMP2	NM_013995.2		c.158G>A	p.Arg53His	missense	Exon 2 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.158G>A	p.Arg53His	missense	Exon 2 of 9	ENSP00000200639.4	P13473-1
LAMP2	ENST00000434600.6	TSL:1	c.158G>A	p.Arg53His	missense	Exon 2 of 9	ENSP00000408411.2	P13473-3
LAMP2	ENST00000371335.4	TSL:1	c.158G>A	p.Arg53His	missense	Exon 2 of 9	ENSP00000360386.4	P13473-2

Frequencies

GnomAD3 genomes

AF:

0.0000630

AC:

AN:

111161

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000131

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00111

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000111

AC:

AN:

171929

AF XY:

0.000173

show subpopulations

Gnomad AFR exome

AF:

0.000157

Gnomad AMR exome

AF:

0.00

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:

0.00

GnomAD4 exome

AF:

0.0000592

AC:

AN:

1030666

Hom.:

Cov.:

AF XY:

0.000120

AC XY:

AN XY:

315886

show subpopulations

African (AFR)

AF:

0.0000398

AC:

AN:

25108

American (AMR)

AF:

0.00

AC:

AN:

34386

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

18764

East Asian (EAS)

AF:

0.000101

AC:

AN:

29707

South Asian (SAS)

AF:

0.000960

AC:

AN:

49991

European-Finnish (FIN)

AF:

0.00

AC:

AN:

39894

Middle Eastern (MID)

AF:

0.00

AC:

AN:

2936

European-Non Finnish (NFE)

AF:

0.00000890

AC:

AN:

786187

Other (OTH)

AF:

0.0000458

AC:

AN:

43693

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.477

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:

0.0000629

AC:

AN:

111203

Hom.:

Cov.:

AF XY:

0.0000897

AC XY:

AN XY:

33447

show subpopulations

African (AFR)

AF:

0.000131

AC:

AN:

30642

American (AMR)

AF:

0.00

AC:

AN:

10422

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2646

East Asian (EAS)

AF:

0.00

AC:

AN:

3559

South Asian (SAS)

AF:

0.00112

AC:

AN:

2682

European-Finnish (FIN)

AF:

0.00

AC:

AN:

5832

Middle Eastern (MID)

AF:

0.00

AC:

AN:

212

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

53028

Other (OTH)

AF:

0.00

AC:

AN:

1497

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.450

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

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:

0.00

Hom.:

Bravo

AF:

0.0000302

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Cardiovascular phenotype (1)

Danon disease (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.063

CardioboostCm

Benign

0.0027

BayesDel_addAF

Benign

-0.75

BayesDel_noAF

Benign

-0.91

CADD

Benign

0.012

(source)

DANN

Benign

0.79

DEOGEN2

Benign

0.29

FATHMM_MKL

Benign

0.0028

LIST_S2

Benign

0.30

M_CAP

Benign

0.0034

MetaRNN

Benign

0.026

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.29

PhyloP100

-4.4

PrimateAI

Benign

0.23

PROVEAN

Benign

-0.53

REVEL

Benign

0.015

Sift

Benign

0.14

Sift4G

Benign

0.12

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.028

gMVP

0.27

Mutation Taster

=98/2

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

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