Genetic Variant LAMP2:p.Val397Leu (chrX-120439198-C-A) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_013995.2(LAMP2):c.1189G>T(p.Val397Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000913 in 1,094,911 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V397I) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 23)

Exomes 𝑓: 9.1e-7 ( 0 hom. 0 hem. )

Consequence

LAMP2
NM_013995.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.200

Publications

3 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: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.03938362).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_013995.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
LAMP2	NM_002294.3	MANE Select	c.1093+2532G>T		intron	N/A	NP_002285.1
LAMP2	NM_013995.2		c.1189G>T	p.Val397Leu	missense	Exon 9 of 9	NP_054701.1
LAMP2	NM_001122606.1		c.1093+2532G>T		intron	N/A	NP_001116078.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
LAMP2	ENST00000371335.4	TSL:1	c.1189G>T	p.Val397Leu	missense	Exon 9 of 9	ENSP00000360386.4
LAMP2	ENST00000200639.9	TSL:1 MANE Select	c.1093+2532G>T		intron	N/A	ENSP00000200639.4
LAMP2	ENST00000434600.6	TSL:1	c.1093+2532G>T		intron	N/A	ENSP00000408411.2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

9.13e-7

AC:

AN:

1094911

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

360397

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26336

American (AMR)

AF:

0.00

AC:

AN:

35196

Ashkenazi Jewish (ASJ)

AF:

0.0000517

AC:

AN:

19349

East Asian (EAS)

AF:

0.00

AC:

AN:

30142

South Asian (SAS)

AF:

0.00

AC:

AN:

54078

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40517

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4126

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

839178

Other (OTH)

AF:

0.00

AC:

AN:

45989

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

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

Cov.:

ClinVar

ClinVar submissions as Germline

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

Danon disease (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.057

BayesDel_addAF

Benign

-0.45

BayesDel_noAF

Benign

-0.88

CADD

Benign

(source)

DANN

Benign

0.51

FATHMM_MKL

Benign

0.70

LIST_S2

Benign

0.082

M_CAP

Benign

0.0082

MetaRNN

Benign

0.039

MetaSVM

Benign

-0.95

PhyloP100

0.20

PROVEAN

Benign

1.6

REVEL

Benign

0.057

Sift

Benign

1.0

Sift4G

Benign

1.0

Polyphen

0.0

Vest4

0.054

MVP

0.35

ClinPred

0.17

GERP RS

2.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over