rs397516741

Variant names:

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The NM_002294.3(LAMP2):c.299C>T(p.Ala100Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000489 in 1,207,540 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 16 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 Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. A100A) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000045 ( 0 hom., 3 hem., cov: 20)

Exomes 𝑓: 0.000049 ( 0 hom. 13 hem. )

Consequence

LAMP2
NM_002294.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 2.09

Publications

0 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 -16 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.026088).

BP6

Variant X-120455455-G-A is Benign according to our data. Variant chrX-120455455-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 44424.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High Hemizygotes in GnomAd4 at 3 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LAMP2	NM_002294.3 link	c.299C>T	p.Ala100Val	missense_variant	Exon 3 of 9	ENST00000200639.9	NP_002285.1	P13473-1
LAMP2	NM_001122606.1 link	c.299C>T	p.Ala100Val	missense_variant	Exon 3 of 9		NP_001116078.1	P13473-3
LAMP2	NM_013995.2 link	c.299C>T	p.Ala100Val	missense_variant	Exon 3 of 9		NP_054701.1	P13473-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
LAMP2	ENST00000200639.9 link	c.299C>T	p.Ala100Val	missense_variant	Exon 3 of 9	1	NM_002294.3	ENSP00000200639.4	P13473-1
LAMP2	ENST00000434600.6 link	c.299C>T	p.Ala100Val	missense_variant	Exon 3 of 9	1		ENSP00000408411.2	P13473-3
LAMP2	ENST00000371335.4 link	c.299C>T	p.Ala100Val	missense_variant	Exon 3 of 9	1		ENSP00000360386.4	P13473-2
LAMP2	ENST00000706600.1 link	c.299C>T	p.Ala100Val	missense_variant	Exon 3 of 9			ENSP00000516464.1	A0A9L9PXQ4

Frequencies

GnomAD3 genomes

AF:

0.0000451

AC:

AN:

110897

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000329

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000378

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000566

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000491

AC:

AN:

183472

AF XY:

0.0000736

show subpopulations

Gnomad AFR exome

AF:

0.00

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:

0.0000977

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000492

AC:

AN:

1096590

Hom.:

Cov.:

AF XY:

0.0000359

AC XY:

AN XY:

361970

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26373

American (AMR)

AF:

0.00

AC:

AN:

35206

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19369

East Asian (EAS)

AF:

0.00

AC:

AN:

30197

South Asian (SAS)

AF:

0.0000185

AC:

AN:

54109

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40534

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4136

European-Non Finnish (NFE)

AF:

0.0000607

AC:

AN:

840616

Other (OTH)

AF:

0.0000434

AC:

AN:

46050

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.454

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:

0.0000451

AC:

AN:

110950

Hom.:

Cov.:

AF XY:

0.0000904

AC XY:

AN XY:

33184

show subpopulations

African (AFR)

AF:

0.0000328

AC:

AN:

30508

American (AMR)

AF:

0.00

AC:

AN:

10328

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2641

East Asian (EAS)

AF:

0.00

AC:

AN:

3542

South Asian (SAS)

AF:

0.000380

AC:

AN:

2633

European-Finnish (FIN)

AF:

0.00

AC:

AN:

5920

Middle Eastern (MID)

AF:

0.00

AC:

AN:

216

European-Non Finnish (NFE)

AF:

0.0000566

AC:

AN:

52983

Other (OTH)

AF:

0.00

AC:

AN:

1496

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.600

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:

0.0000340

ExAC

AF:

0.0000494

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.000119

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

Nov 14, 2017

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Apr 11, 2012

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Ala100Val in 3 of LAMP2: This variant is not expected to have clinical significa nce because it has been previously reported in a phenotypically unaffected male who was hemizygous for this variant. Ala100Val in 3 of LAMP2 (allele frequency = n/a) -

Danon disease

Benign:2

Aug 17, 2021

Fulgent Genetics, Fulgent Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Dec 07, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:1

Jun 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

LAMP2: BP4, BS2 -

Cardiovascular phenotype

Benign:1

Dec 18, 2019

Ambry Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as likely 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

AlphaMissense

Benign

0.071

CardioboostCm

Benign

0.0021

BayesDel_addAF

Benign

-0.67

BayesDel_noAF

Benign

-1.0

CADD

Benign

4.1

(source)

DANN

Benign

0.17

DEOGEN2

Benign

0.26

.;T;.

FATHMM_MKL

Benign

0.0037

LIST_S2

Benign

0.80

T;T;T

M_CAP

Benign

0.0029

MetaRNN

Benign

0.026

T;T;T

MetaSVM

Benign

-0.98

MutationAssessor

Benign

-1.8

N;N;N

PhyloP100

2.1

PrimateAI

Benign

0.27

PROVEAN

Benign

2.0

N;N;N

REVEL

Benign

0.023

Sift

Benign

1.0

T;T;T

Sift4G

Benign

1.0

T;T;T

Polyphen

0.0010, 0.0020

.;B;B

Vest4

0.049

MutPred

0.34

Gain of methylation at K104 (P = 0.0916);Gain of methylation at K104 (P = 0.0916);Gain of methylation at K104 (P = 0.0916);

MVP

0.15

MPC

0.25

ClinPred

0.016

GERP RS

2.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.031

gMVP

0.28

Mutation Taster

=100/0

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over