chrX-120469173-C-G

Variant names:

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_002294.3(LAMP2):c.-4G>C variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000188 in 1,210,408 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 77 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 0.000089 ( 0 hom., 3 hem., cov: 24)

Exomes 𝑓: 0.00020 ( 0 hom. 74 hem. )

Consequence

LAMP2
NM_002294.3 5_prime_UTR

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:6

Conservation

PhyloP100: -1.48

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -9 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.59).

BP6

Variant X-120469173-C-G is Benign according to our data. Variant chrX-120469173-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 44415.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=2, Benign=3}. Variant chrX-120469173-C-G is described in Lovd as [Likely_benign].

BS2

High Hemizygotes in GnomAd4 at 3 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
LAMP2	NM_002294.3 link	c.-4G>C	5_prime_UTR_variant	Exon 1 of 9	ENST00000200639.9	NP_002285.1	P13473-1
LAMP2	NM_001122606.1 link	c.-4G>C	5_prime_UTR_variant	Exon 1 of 9		NP_001116078.1	P13473-3
LAMP2	NM_013995.2 link	c.-4G>C	5_prime_UTR_variant	Exon 1 of 9		NP_054701.1	P13473-2

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
LAMP2	ENST00000200639.9 link	c.-4G>C	5_prime_UTR_variant	Exon 1 of 9	1	NM_002294.3	ENSP00000200639.4	P13473-1
LAMP2	ENST00000434600.6 link	c.-4G>C	5_prime_UTR_variant	Exon 1 of 9	1		ENSP00000408411.2	P13473-3
LAMP2	ENST00000371335.4 link	c.-4G>C	5_prime_UTR_variant	Exon 1 of 9	1		ENSP00000360386.4	P13473-2
LAMP2	ENST00000706600.1 link	c.-4G>C	5_prime_UTR_variant	Exon 1 of 9			ENSP00000516464.1	A0A9L9PXQ4

Frequencies

GnomAD3 genomes

AF:

0.0000889

AC:

AN:

112529

Hom.:

Cov.:

AF XY:

0.0000865

AC XY:

AN XY:

34683

show subpopulations

Gnomad AFR

AF:

0.0000964

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.000754

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000565

Gnomad OTH

AF:

0.00132

GnomAD3 exomes

AF:

0.000203

AC:

AN:

182071

Hom.:

AF XY:

0.000238

AC XY:

AN XY:

67157

show subpopulations

Gnomad AFR exome

AF:

0.000154

Gnomad AMR exome

AF:

0.000110

Gnomad ASJ exome

AF:

0.00174

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000251

Gnomad NFE exome

AF:

0.000161

Gnomad OTH exome

AF:

0.000445

GnomAD4 exome

AF:

0.000199

AC:

218

AN:

1097879

Hom.:

Cov.:

AF XY:

0.000204

AC XY:

AN XY:

363301

show subpopulations

Gnomad4 AFR exome

AF:

0.0000758

Gnomad4 AMR exome

AF:

0.0000852

Gnomad4 ASJ exome

AF:

0.00243

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000369

Gnomad4 FIN exome

AF:

0.000222

Gnomad4 NFE exome

AF:

0.000167

Gnomad4 OTH exome

AF:

0.000304

GnomAD4 genome

AF:

0.0000889

AC:

AN:

112529

Hom.:

Cov.:

AF XY:

0.0000865

AC XY:

AN XY:

34683

show subpopulations

Gnomad4 AFR

AF:

0.0000964

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.000754

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000565

Gnomad4 OTH

AF:

0.00132

Alfa

AF:

0.000391

Hom.:

Bravo

AF:

0.000132

EpiCase

AF:

0.000109

EpiControl

AF:

0.000356

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:6

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Uncertain:1Benign:2

Oct 16, 2012

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The -4G>C variant in LAMP2 has not been reported in the literature nor previousl y identified by our laboratory. This variant has been identified in 1/6723 Europ ean American chromosomes from a broad population by the NHLBI Exome Sequencing P roject (http://evs.gs.washington.edu/EVS/; dbSNP rs200297370). This variant is l ocated in the 5' UTR of the LAMP2 gene. Although this region can contain regulat ory elements, there is no obvious predicted effect of this variant and there are no other pathogenic variants that have been reported in the 5'UTR region of the LAMP2 gene. In summary, additional information is needed to fully assess the cl inical significance of the -4G>C variant. -

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jul 30, 2013

GeneDx

Significance: 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. -

not provided

Benign:2

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Apr 01, 2022

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

LAMP2: BS2 -

Hypertrophic cardiomyopathy

Uncertain:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Danon disease

Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Cardiovascular phenotype

Benign:1

Apr 13, 2017

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as 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

BayesDel_noAF

Benign

-0.59

CADD

Benign

3.3

DANN

Benign

0.93

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over