rs3180515

Variant names:

• chrX-120469138-C-A
• rs3180515
• NM_002294.3:c.32G>T

Your query was ambiguous. Multiple possible variants found:

• chrX-120469138-C-A
• chrX-120469138-C-G

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP6 BS2

The NM_002294.3(LAMP2):​c.32G>T​(p.Gly11Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000729 in 1,098,126 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 3 hemizygotes in GnomAD. 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. G11S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.0000073 (0 hom. 3 hem.)
• Consequence: LAMP2 NM_002294.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:2
• Conservation: PhyloP100: 0.901
• Publications: 2 publications found

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

ACMG classification

Our verdict: Likely_benign. The variant received -5 ACMG points.

• BP6: Variant X-120469138-C-A is Benign according to our data. Variant chrX-120469138-C-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 163820.
• BS2: High Hemizygotes in GnomAdExome4 at 3 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LAMP2	NM_002294.3	c.32G>T	p.Gly11Val	missense_variant	Exon 1 of 9	ENST00000200639.9	NP_002285.1
LAMP2	NM_001122606.1	c.32G>T	p.Gly11Val	missense_variant	Exon 1 of 9		NP_001116078.1
LAMP2	NM_013995.2	c.32G>T	p.Gly11Val	missense_variant	Exon 1 of 9		NP_054701.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LAMP2	ENST00000200639.9	c.32G>T	p.Gly11Val	missense_variant	Exon 1 of 9	1	NM_002294.3	ENSP00000200639.4
LAMP2	ENST00000434600.6	c.32G>T	p.Gly11Val	missense_variant	Exon 1 of 9	1		ENSP00000408411.2
LAMP2	ENST00000371335.4	c.32G>T	p.Gly11Val	missense_variant	Exon 1 of 9	1		ENSP00000360386.4
LAMP2	ENST00000706600.1	c.32G>T	p.Gly11Val	missense_variant	Exon 1 of 9			ENSP00000516464.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome AF: 0.00000729 AC: 8 AN: 1098126 Hom.: 0 Cov.: 30 AF XY: 0.00000825 AC XY: 3 AN XY: 363514

African (AFR) AF: 0.00 AC: 0 AN: 26398

American (AMR) AF: 0.00 AC: 0 AN: 35207

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19383

East Asian (EAS) AF: 0.00 AC: 0 AN: 30205

South Asian (SAS) AF: 0.00 AC: 0 AN: 54145

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40516

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4131

European-Non Finnish (NFE) AF: 0.00000950 AC: 8 AN: 842059

Other (OTH) AF: 0.00 AC: 0 AN: 46082

GnomAD4 genome Cov.: 23

Alfa AF: 0.0000358 Hom.: 0

Bravo AF: 0.0000189

EpiCase AF: 0.000109

EpiControl AF: 0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:2

May 06, 2021

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Gly11Val variant in LAMP2 has been identified in at least 1 infant that harbored a disease-causing variant in another cardiomyopathy associated gene (LMM data). This variant has also been reported by other clinical laboratories in ClinVar (Variation ID: 163820) and has been identified in 0.009% (1/10812) of European chromosomes, including 1 hemizygote, by gnomAD (http://gnomad.broadinstitute.org). Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. In summary, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PM2_Supporting. -

Mar 10, 2021

Mayo Clinic Laboratories, Mayo Clinic

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Danon disease Uncertain:1 Benign:1

May 02, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 09, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Primary dilated cardiomyopathy Uncertain:1

Sep 29, 2014

Blueprint Genetics

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Cardiovascular phenotype Benign:1

Dec 09, 2023

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	0.081
CardioboostCm	Benign	0.036
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	19
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.66	.;D;.
FATHMM_MKL	Benign	0.31	N
LIST_S2	Benign	0.81	T;T;T
M_CAP	Uncertain	0.28	D
MetaRNN	Uncertain	0.61	D;D;D
MetaSVM	Benign	-0.65	T
MutationAssessor	Uncertain	2.2	M;M;M
PhyloP100		0.90
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-2.0	N;N;N
REVEL	Benign	0.22
Sift	Pathogenic	0.0	D;D;D
Sift4G	Benign	0.13	T;T;T
Polyphen		1.0	.;D;D
Vest4		0.43
MutPred		0.58		Gain of sheet (P = 0.0477);Gain of sheet (P = 0.0477);Gain of sheet (P = 0.0477);
MVP		0.64
MPC		0.95
ClinPred		0.93	D
GERP RS		4.1
PromoterAI		0.16	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.20
gMVP		0.55
Mutation Taster		=92/8	polymorphism

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

Other links and lift over

dbSNP: rs3180515; hg19: chrX-119602993;