X-120455415-G-C

Position:

• chrX-120455415-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 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. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• 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

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 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/exons	MANE	Protein	UniProt
LAMP2	NM_002294.3	c.339C>G	p.Ser113Arg	missense_variant	3/9	ENST00000200639.9	NP_002285.1
LAMP2	NM_001122606.1	c.339C>G	p.Ser113Arg	missense_variant	3/9		NP_001116078.1
LAMP2	NM_013995.2	c.339C>G	p.Ser113Arg	missense_variant	3/9		NP_054701.1

Ensembl

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

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000238

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 20

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

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 31, 2021

- -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Nov 03, 2017

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	0.26	.;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
MutationTaster	Benign	1.0	N;N;N;N;N
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
Polyphen		0.027, 0.022	.;B;B
Vest4		0.29
MutPred		0.37		Loss of disorder (P = 0.0682);Loss of disorder (P = 0.0682);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

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

Publications

LitVar

Other links and lift over

dbSNP: rs147369153; hg19: chrX-119589270;