rs397516744

Variant names:

• chrX-120455383-G-A
• rs397516744
• NM_002294.3:c.371C>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_002294.3(LAMP2):​c.371C>T​(p.Thr124Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000101 in 1,093,006 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. T124T) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 21)
  • Exomes 𝑓: 0.000010 (0 hom. 1 hem.)
• Consequence: LAMP2 NM_002294.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 0.136
• 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 -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.13170621).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LAMP2	NM_002294.3	c.371C>T	p.Thr124Ile	missense_variant	Exon 3 of 9	ENST00000200639.9	NP_002285.1
LAMP2	NM_001122606.1	c.371C>T	p.Thr124Ile	missense_variant	Exon 3 of 9		NP_001116078.1
LAMP2	NM_013995.2	c.371C>T	p.Thr124Ile	missense_variant	Exon 3 of 9		NP_054701.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LAMP2	ENST00000200639.9	c.371C>T	p.Thr124Ile	missense_variant	Exon 3 of 9	1	NM_002294.3	ENSP00000200639.4
LAMP2	ENST00000434600.6	c.371C>T	p.Thr124Ile	missense_variant	Exon 3 of 9	1		ENSP00000408411.2
LAMP2	ENST00000371335.4	c.371C>T	p.Thr124Ile	missense_variant	Exon 3 of 9	1		ENSP00000360386.4
LAMP2	ENST00000706600.1	c.371C>T	p.Thr124Ile	missense_variant	Exon 3 of 9			ENSP00000516464.1

Frequencies

GnomAD3 genomes Cov.: 21

GnomAD4 exome AF: 0.0000101 AC: 11 AN: 1093006 Hom.: 0 Cov.: 29 AF XY: 0.00000279 AC XY: 1 AN XY: 358626

African (AFR) AF: 0.00 AC: 0 AN: 26304

American (AMR) AF: 0.00 AC: 0 AN: 35201

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19365

East Asian (EAS) AF: 0.00 AC: 0 AN: 30191

South Asian (SAS) AF: 0.00 AC: 0 AN: 54022

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40531

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4122

European-Non Finnish (NFE) AF: 0.0000131 AC: 11 AN: 837331

Other (OTH) AF: 0.00 AC: 0 AN: 45939

GnomAD4 genome Cov.: 21

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:1

Jun 22, 2012

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant classified as Uncertain Significance - Favor Benign. The Thr124Ile varia nt in LAMP2 has not been previously reported, but has previously been identified in one individual with HCM by our laboratory. This variant has not been identif ied in large and broad populations by the NHLBI Exome Sequencing Project (http:/ /evs.gs.washington.edu/EVS). This low frequency supports a pathogenic role. Howe ver, threonine (Thr) at position 124 is not conserved in mammals or chicken, red ucing the likelihood that the change is pathogenic. In addition, pathogenic miss ense variants are rare in the LAMP2 gene, as most disease causing variants lead to a loss of function. Computational analyses (biochemical amino acid properties , AlignGVGD, PolyPhen2, and SIFT) suggest that the Thr124Ile variant may not imp act the protein, though this information is not predictive enough to rule out pa thogenicity. In summary, although this data suggests that the Thr124Ile variant is likely benign, in the absence of additional information its clinical signific ance cannot be determined. -

Cardiovascular phenotype Uncertain:1

May 07, 2020

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.371C>T (p.T124I) alteration is located in exon 3 (coding exon 3) of the LAMP2 gene. This alteration results from a C to T substitution at nucleotide position 371, causing the threonine (T) at amino acid position 124 to be replaced by an isoleucine (I). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.093
CardioboostCm	Benign	0.0018
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.75
CADD	Benign	12
DANN	Uncertain	0.98
DEOGEN2	Benign	0.32	.;T;.
FATHMM_MKL	Benign	0.062	N
LIST_S2	Benign	0.63	T;T;T
M_CAP	Uncertain	0.20	D
MetaRNN	Benign	0.13	T;T;T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	1.5	L;L;L
PhyloP100		0.14
PrimateAI	Benign	0.36	T
PROVEAN	Uncertain	-2.5	D;D;D
REVEL	Benign	0.062
Sift	Benign	0.12	T;T;T
Sift4G	Uncertain	0.032	D;D;D
Polyphen		0.0060, 0.0020	.;B;B
Vest4		0.13
MutPred		0.41		Loss of disorder (P = 0.0188);Loss of disorder (P = 0.0188);Loss of disorder (P = 0.0188);
MVP		0.29
MPC		0.27
ClinPred		0.11	T
GERP RS		-0.023
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.099
gMVP		0.31
Mutation Taster		=93/7	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: rs397516744; hg19: chrX-119589238;