X-120439186-T-C

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2

The ENST00000371335.4(LAMP2):ā€‹c.1201A>Gā€‹(p.Arg401Gly) variant causes a missense change. The variant allele was found at a frequency of 0.000188 in 1,208,176 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 70 hemizygotes in GnomAD. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: š‘“ 0.000080 ( 0 hom., 2 hem., cov: 24)
Exomes š‘“: 0.00020 ( 0 hom. 68 hem. )

Consequence

LAMP2
ENST00000371335.4 missense

Scores

2
7
4

Clinical Significance

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

Conservation

PhyloP100: 5.76
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -4 ACMG points.

BS2
High Hemizygotes in GnomAd4 at 2 XL gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
LAMP2NM_002294.3 linkuse as main transcriptc.1093+2544A>G intron_variant ENST00000200639.9 NP_002285.1
LAMP2NM_013995.2 linkuse as main transcriptc.1201A>G p.Arg401Gly missense_variant 9/9 NP_054701.1
LAMP2NM_001122606.1 linkuse as main transcriptc.1093+2544A>G intron_variant NP_001116078.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
LAMP2ENST00000200639.9 linkuse as main transcriptc.1093+2544A>G intron_variant 1 NM_002294.3 ENSP00000200639 P3P13473-1

Frequencies

GnomAD3 genomes
AF:
0.0000803
AC:
9
AN:
112043
Hom.:
0
Cov.:
24
AF XY:
0.0000585
AC XY:
2
AN XY:
34203
show subpopulations
Gnomad AFR
AF:
0.0000324
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000951
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:
0.000132
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000545
AC:
10
AN:
183391
Hom.:
0
AF XY:
0.0000737
AC XY:
5
AN XY:
67869
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000365
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.000110
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.000199
AC:
218
AN:
1096133
Hom.:
0
Cov.:
28
AF XY:
0.000188
AC XY:
68
AN XY:
361579
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000284
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.000252
Gnomad4 OTH exome
AF:
0.000109
GnomAD4 genome
AF:
0.0000803
AC:
9
AN:
112043
Hom.:
0
Cov.:
24
AF XY:
0.0000585
AC XY:
2
AN XY:
34203
show subpopulations
Gnomad4 AFR
AF:
0.0000324
Gnomad4 AMR
AF:
0.0000951
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000132
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000427
Hom.:
3
Bravo
AF:
0.0000793
TwinsUK
AF:
0.00
AC:
0
ALSPAC
AF:
0.000346
AC:
1
ExAC
AF:
0.0000741
AC:
9
EpiCase
AF:
0.000218
EpiControl
AF:
0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:2Benign:2
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

Danon disease Uncertain:1Benign:1
Benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpAug 09, 2022- -
Uncertain significance, criteria provided, single submitterclinical testingFulgent Genetics, Fulgent GeneticsOct 12, 2021- -
not provided Uncertain:1Benign:1
Uncertain significance, criteria provided, single submitterclinical testingGeneDxAug 22, 2022Located in an alternate transcript of the LAMP2 gene and has been reported previously as an isoform-specific variant; however, no additional information regarding the phenotype or the variant was provided (D'souza et al., 2014); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 25228319) -
Likely benign, criteria provided, single submitterclinical testingCeGaT Center for Human Genetics TuebingenDec 01, 2023LAMP2: BP4, BS2 -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Benign
-0.27
T
BayesDel_noAF
Benign
-0.41
CADD
Benign
22
DANN
Uncertain
1.0
FATHMM_MKL
Uncertain
0.96
D
LIST_S2
Uncertain
0.89
D
M_CAP
Pathogenic
0.70
D
MetaRNN
Uncertain
0.59
D
MetaSVM
Benign
-0.46
T
MutationTaster
Benign
1.0
D;D;D;D;D
PROVEAN
Pathogenic
-5.0
D
REVEL
Uncertain
0.44
Sift
Uncertain
0.0030
D
Sift4G
Uncertain
0.0060
D
Polyphen
0.89
P
Vest4
0.44
MVP
0.53
ClinPred
0.38
T
GERP RS
5.5
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs777128122; hg19: chrX-119573041; API