chrX-120448001-G-T

Variant names:

• chrX-120448001-G-T
• rs1033442580
• NM_002294.3:c.581C>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001122606.1(LAMP2):​c.581C>A​(p.Thr194Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T194I) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000090 (0 hom., 1 hem., cov: 23)
  • Failed GnomAD Quality Control
• Consequence: LAMP2 NM_001122606.1 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 0.371
• Publications: 0 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.19597664).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001122606.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LAMP2	NM_002294.3	MANE Select	c.581C>A	p.Thr194Asn	missense	Exon 5 of 9	NP_002285.1
	LAMP2	NM_001122606.1		c.581C>A	p.Thr194Asn	missense	Exon 5 of 9	NP_001116078.1
	LAMP2	NM_013995.2		c.581C>A	p.Thr194Asn	missense	Exon 5 of 9	NP_054701.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LAMP2	ENST00000200639.9	TSL:1 MANE Select	c.581C>A	p.Thr194Asn	missense	Exon 5 of 9	ENSP00000200639.4
	LAMP2	ENST00000434600.6	TSL:1	c.581C>A	p.Thr194Asn	missense	Exon 5 of 9	ENSP00000408411.2
	LAMP2	ENST00000371335.4	TSL:1	c.581C>A	p.Thr194Asn	missense	Exon 5 of 9	ENSP00000360386.4

Frequencies

GnomAD3 genomes AF: 0.00000900 AC: 1 AN: 111160 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000958

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 29

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000900 AC: 1 AN: 111160 Hom.: 0 Cov.: 23 AF XY: 0.0000300 AC XY: 1 AN XY: 33372

African (AFR) AF: 0.00 AC: 0 AN: 30483

American (AMR) AF: 0.0000958 AC: 1 AN: 10434

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2642

East Asian (EAS) AF: 0.00 AC: 0 AN: 3540

South Asian (SAS) AF: 0.00 AC: 0 AN: 2668

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5905

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 237

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 53071

Other (OTH) AF: 0.00 AC: 0 AN: 1498

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000151

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	2	-	Danon disease (2)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.069
CardioboostCm	Benign	0.00096
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.80
CADD	Benign	5.3
DANN	Benign	0.85
DEOGEN2	Benign	0.34	T
FATHMM_MKL	Benign	0.16	N
LIST_S2	Benign	0.60	T
M_CAP	Uncertain	0.20	D
MetaRNN	Benign	0.20	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	1.9	L
PhyloP100		0.37
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-1.9	N
REVEL	Benign	0.064
Sift	Benign	0.10	T
Sift4G	Benign	0.063	T
Polyphen		0.011	B
Vest4		0.12
MutPred		0.60		Loss of glycosylation at T194 (P = 0.0487)
MVP		0.58
MPC		0.30
ClinPred		0.065	T
GERP RS		0.77
Varity_R		0.19
gMVP		0.66
Mutation Taster		=96/4	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: rs1033442580; hg19: chrX-119581856;