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: 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=0.1961604).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LAMP2	NM_002294.3	c.339C>G	p.Ser113Arg	missense_variant	Exon 3 of 9	ENST00000200639.9	NP_002285.1
LAMP2	NM_001122606.1	c.339C>G	p.Ser113Arg	missense_variant	Exon 3 of 9		NP_001116078.1
LAMP2	NM_013995.2	c.339C>G	p.Ser113Arg	missense_variant	Exon 3 of 9		NP_054701.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LAMP2	ENST00000200639.9	c.339C>G	p.Ser113Arg	missense_variant	Exon 3 of 9	1	NM_002294.3	ENSP00000200639.4
LAMP2	ENST00000434600.6	c.339C>G	p.Ser113Arg	missense_variant	Exon 3 of 9	1		ENSP00000408411.2
LAMP2	ENST00000371335.4	c.339C>G	p.Ser113Arg	missense_variant	Exon 3 of 9	1		ENSP00000360386.4
LAMP2	ENST00000706600.1	c.339C>G	p.Ser113Arg	missense_variant	Exon 3 of 9			ENSP00000516464.1

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

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Danon disease Uncertain:1

Aug 31, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Uncertain:1

Nov 03, 2017

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The S113R variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The S113R variant is not observed in large population cohorts (Lek et al., 2016). The S113R variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is not conserved. The majority of in silico analyses predict this variant likely does not alter the protein structure/function. In summary, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.

Computational scores

Source: dbNSFP v4.3

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	0.0	.;T;.
FATHMM_MKL	Benign	0.091	N
LIST_S2	Benign	0.57	T;T;T
M_CAP	Uncertain	0.28	D
MetaRNN	Benign	0.20	T;T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	1.8	L;L;L
PhyloP100		0.0050
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-1.6	N;N;N
REVEL	Benign	0.092
Sift	Benign	0.49	T;T;T
Sift4G	Benign	0.31	T;T;T
Vest4		0.29
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;