rs960241982

Positions:

• chrX-120441843-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_002294.3(LAMP2):​c.980G>T​(p.Ser327Ile) variant causes a missense change. The variant allele was found at a frequency of 0.000000912 in 1,096,524 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 22)
  • Exomes 𝑓: 9.1e-7 (0 hom. 0 hem.)
• Consequence: LAMP2 NM_002294.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.69

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 Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.858

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LAMP2	NM_002294.3	c.980G>T	p.Ser327Ile	missense_variant	8/9	ENST00000200639.9	NP_002285.1
LAMP2	NM_001122606.1	c.980G>T	p.Ser327Ile	missense_variant	8/9		NP_001116078.1
LAMP2	NM_013995.2	c.980G>T	p.Ser327Ile	missense_variant	8/9		NP_054701.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LAMP2	ENST00000200639.9	c.980G>T	p.Ser327Ile	missense_variant	8/9	1	NM_002294.3	ENSP00000200639.4

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD3 exomes AF: 0.00000545 AC: 1 AN: 183468 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 67904

Gnomad AFR exome AF: 0.0000760

Gnomad AMR exome AF: 0.00

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 9.12e-7 AC: 1 AN: 1096524 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 361894

Gnomad4 AFR exome AF: 0.0000379

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 22

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Danon disease Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Mar 18, 2022

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 566749). This missense change has been observed to be homozygous or hemizygous in an individual who did not have the expected clinical features for that genetic result (Invitae). This variant has not been reported in the literature in individuals affected with LAMP2-related conditions. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This sequence change replaces serine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 327 of the LAMP2 protein (p.Ser327Ile). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.58
CardioboostCm	Uncertain	0.28
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.070
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.42	.;T;.
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.90	D;D;D
M_CAP	Pathogenic	0.69	D
MetaRNN	Pathogenic	0.86	D;D;D
MetaSVM	Benign	-0.61	T
MutationAssessor	Pathogenic	3.0	M;M;M
PrimateAI	Uncertain	0.50	T
PROVEAN	Pathogenic	-4.5	D;D;D
REVEL	Uncertain	0.39
Sift	Uncertain	0.0020	D;D;D
Sift4G	Uncertain	0.0020	D;D;D
Polyphen		1.0	.;D;D
Vest4		0.58
MutPred		0.71		Loss of disorder (P = 0.032);Loss of disorder (P = 0.032);Loss of disorder (P = 0.032);
MVP		0.70
MPC		0.97
ClinPred		0.97	D
GERP RS		5.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.97
gMVP		0.83

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: rs960241982; hg19: chrX-119575698;