NM_002294.3:c.928G>A

Variant names:

• chrX-120442599-C-T
• rs104894858
• NM_002294.3:c.928G>A

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_002294.3(LAMP2):​c.928G>A​(p.Val310Ile) variant causes a missense, splice region change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V310L) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 22)
• Consequence: LAMP2 NM_002294.3 missense, splice_region
• Scores: Splicing: ADA: 0.9999
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:9
• Conservation: PhyloP100: 4.51
• Publications: 19 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: G2P, Labcorp Genetics (formerly Invitae), Orphanet, ClinGen, Genomics England PanelApp

ACMG classification

Our verdict: Pathogenic. The variant received 16 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrX-120442599-C-G is described in ClinVar as Pathogenic. ClinVar VariationId is 1452436.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant X-120442599-C-T is Pathogenic according to our data. Variant chrX-120442599-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 9982.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002294.3. 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.928G>A	p.Val310Ile	missense splice_region	Exon 7 of 9	NP_002285.1	P13473-1
	LAMP2	NM_001122606.1		c.928G>A	p.Val310Ile	missense splice_region	Exon 7 of 9	NP_001116078.1	P13473-3
	LAMP2	NM_013995.2		c.928G>A	p.Val310Ile	missense splice_region	Exon 7 of 9	NP_054701.1	P13473-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LAMP2	ENST00000200639.9	TSL:1 MANE Select	c.928G>A	p.Val310Ile	missense splice_region	Exon 7 of 9	ENSP00000200639.4	P13473-1
	LAMP2	ENST00000434600.6	TSL:1	c.928G>A	p.Val310Ile	missense splice_region	Exon 7 of 9	ENSP00000408411.2	P13473-3
	LAMP2	ENST00000371335.4	TSL:1	c.928G>A	p.Val310Ile	missense splice_region	Exon 7 of 9	ENSP00000360386.4	P13473-2

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 28

GnomAD4 genome Cov.: 22

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
4	-	-	not provided (4)
3	-	-	Danon disease (3)
1	-	-	Cardiovascular phenotype (1)
1	-	-	Hypertrophic cardiomyopathy;C0878677:Danon disease (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.085
CardioboostCm	Uncertain	0.76
BayesDel_addAF	Benign	-0.018	T
BayesDel_noAF	Benign	-0.26
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.21	T
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.84	T
M_CAP	Uncertain	0.26	D
MetaRNN	Pathogenic	0.89	D
MetaSVM	Benign	-0.84	T
MutationAssessor	Uncertain	2.6	M
PhyloP100		4.5
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-0.74	N
REVEL	Benign	0.19
Sift	Benign	0.25	T
Sift4G	Benign	0.20	T
Polyphen		0.071	B
Vest4		0.69
MutPred		0.82		Gain of sheet (P = 0.0827)
MVP		0.88
MPC		0.51
ClinPred		0.88	D
GERP RS		5.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.29
gMVP		0.16
Mutation Taster		=2/98	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.99
Splicevardb		3.0
SpliceAI score (max)		0.81		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.81		Position offset: 0

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs104894858; hg19: chrX-119576454; COSMIC: COSV52355486;