X-120455415-G-C

Variant names:

• chrX-120455415-G-C
• rs147369153
• NM_002294.3:c.339C>G

Variant summary

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

The NM_002294.3(LAMP2):​c.339C>G​(p.Ser113Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000182 in 1,097,119 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. 14/22 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. S113S) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 20)
  • Exomes 𝑓: 0.0000018 (0 hom. 1 hem.)
• Consequence: LAMP2 NM_002294.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 0.00500
• Publications: 4 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: 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=0.1961604).

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.339C>G	p.Ser113Arg	missense	Exon 3 of 9	NP_002285.1	P13473-1
	LAMP2	NM_001122606.1		c.339C>G	p.Ser113Arg	missense	Exon 3 of 9	NP_001116078.1	P13473-3
	LAMP2	NM_013995.2		c.339C>G	p.Ser113Arg	missense	Exon 3 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.339C>G	p.Ser113Arg	missense	Exon 3 of 9	ENSP00000200639.4	P13473-1
	LAMP2	ENST00000434600.6	TSL:1	c.339C>G	p.Ser113Arg	missense	Exon 3 of 9	ENSP00000408411.2	P13473-3
	LAMP2	ENST00000371335.4	TSL:1	c.339C>G	p.Ser113Arg	missense	Exon 3 of 9	ENSP00000360386.4	P13473-2

Frequencies

GnomAD3 genomes Cov.: 20

GnomAD4 exome AF: 0.00000182 AC: 2 AN: 1097119 Hom.: 0 Cov.: 30 AF XY: 0.00000276 AC XY: 1 AN XY: 362487

African (AFR) AF: 0.00 AC: 0 AN: 26378

American (AMR) AF: 0.00 AC: 0 AN: 35206

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19380

East Asian (EAS) AF: 0.00 AC: 0 AN: 30198

South Asian (SAS) AF: 0.00 AC: 0 AN: 54128

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40532

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4134

European-Non Finnish (NFE) AF: 0.00000238 AC: 2 AN: 841104

Other (OTH) AF: 0.00 AC: 0 AN: 46059

GnomAD4 genome Cov.: 20

Alfa AF: 0.00 Hom.: 10

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
CardioboostCm	Benign	0.0019
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.70
CADD	Benign	15
DANN	Uncertain	0.98
DEOGEN2	Benign	0.26	T
FATHMM_MKL	Benign	0.091	N
LIST_S2	Benign	0.57	T
M_CAP	Uncertain	0.28	D
MetaRNN	Benign	0.20	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	1.8	L
PhyloP100		0.0050
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-1.6	N
REVEL	Benign	0.092
Sift	Benign	0.49	T
Sift4G	Benign	0.31	T
Polyphen		0.027	B
Vest4		0.29
MutPred		0.37		Loss of disorder (P = 0.0682)
MVP		0.56
MPC		0.32
ClinPred		0.10	T
GERP RS		-1.8
Varity_R		0.33
gMVP		0.44
Mutation Taster		=96/4	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.14		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: rs147369153; hg19: chrX-119589270; COSMIC: COSV106326859;