rs397516744

Positions:

• chrX-120455383-G-A

Variant summary

Our verdict is Likely benign. Variant got -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. 12/21 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

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]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LAMP2	NM_002294.3	c.371C>T	p.Thr124Ile	missense_variant	3/9	ENST00000200639.9
LAMP2	NM_001122606.1	c.371C>T	p.Thr124Ile	missense_variant	3/9
LAMP2	NM_013995.2	c.371C>T	p.Thr124Ile	missense_variant	3/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LAMP2	ENST00000200639.9	c.371C>T	p.Thr124Ile	missense_variant	3/9	1	NM_002294.3	P3
LAMP2	ENST00000434600.6	c.371C>T	p.Thr124Ile	missense_variant	3/9	1		A1
LAMP2	ENST00000371335.4	c.371C>T	p.Thr124Ile	missense_variant	3/9	1		A1
LAMP2	ENST00000706600.1	c.371C>T	p.Thr124Ile	missense_variant	3/9

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

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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: 0.0000131

Gnomad4 OTH exome AF: 0.00

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

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jun 22, 2012

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

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 07, 2020

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
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
MutationTaster	Benign	1.0	N;N;N;N;N
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

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

Other links and lift over

dbSNP: rs397516744; hg19: chrX-119589238;