chrX-120448016-C-T

Variant names:

• chrX-120448016-C-T
• rs750457485
• NM_002294.3:c.566G>A

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_001122606.1(LAMP2):​c.566G>A​(p.Cys189Tyr) 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 pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 9.1e-7 (0 hom. 1 hem.)
  • Failed GnomAD Quality Control
• Consequence: LAMP2 NM_001122606.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.39
• 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: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.968

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.566G>A	p.Cys189Tyr	missense	Exon 5 of 9	NP_002285.1
	LAMP2	NM_001122606.1		c.566G>A	p.Cys189Tyr	missense	Exon 5 of 9	NP_001116078.1
	LAMP2	NM_013995.2		c.566G>A	p.Cys189Tyr	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.566G>A	p.Cys189Tyr	missense	Exon 5 of 9	ENSP00000200639.4
	LAMP2	ENST00000434600.6	TSL:1	c.566G>A	p.Cys189Tyr	missense	Exon 5 of 9	ENSP00000408411.2
	LAMP2	ENST00000371335.4	TSL:1	c.566G>A	p.Cys189Tyr	missense	Exon 5 of 9	ENSP00000360386.4

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD2 exomes AF: 0.00000545 AC: 1 AN: 183432 AF XY: 0.0000147

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 9.13e-7 AC: 1 AN: 1095773 Hom.: 0 Cov.: 29 AF XY: 0.00000277 AC XY: 1 AN XY: 361153

African (AFR) AF: 0.00 AC: 0 AN: 26343

American (AMR) AF: 0.00 AC: 0 AN: 35205

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19364

East Asian (EAS) AF: 0.00 AC: 0 AN: 30194

South Asian (SAS) AF: 0.0000185 AC: 1 AN: 54092

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40512

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 839924

Other (OTH) AF: 0.00 AC: 0 AN: 46017

GnomAD4 genome Cov.: 23

ExAC AF: 0.0000165 AC: 2

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Danon disease (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.95
CardioboostCm	Uncertain	0.11
BayesDel_addAF	Benign	-0.020	T
BayesDel_noAF	Benign	-0.12
CADD	Uncertain	24
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.50	D
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.85	D
M_CAP	Pathogenic	0.62	D
MetaRNN	Pathogenic	0.97	D
MetaSVM	Benign	-0.43	T
MutationAssessor	Pathogenic	3.4	M
PhyloP100		3.4
PrimateAI	Uncertain	0.70	T
PROVEAN	Pathogenic	-10	D
REVEL	Uncertain	0.40
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.26
MutPred		0.94		Loss of methylation at K191 (P = 0.0571)
MVP		0.82
MPC		1.2
ClinPred		0.91	D
GERP RS		6.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.97
gMVP		0.99
Mutation Taster		=94/6	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs750457485; hg19: chrX-119581871;