NM_002294.3:c.333T>C

Variant names:

• chrX-120455421-A-G
• rs397516742
• NM_002294.3:c.333T>C

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 2P and 13B. PM2 BP4_Strong BP6_Very_Strong BP7

The NM_002294.3(LAMP2):​c.333T>C​(p.Ile111Ile) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000364 in 1,097,456 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: not found (cov: 20)
  • Exomes 𝑓: 0.0000036 (0 hom. 0 hem.)
• Consequence: LAMP2 NM_002294.3 synonymous
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.654
• 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: G2P, Labcorp Genetics (formerly Invitae), Orphanet, ClinGen, Genomics England PanelApp

ACMG classification

Our verdict: Benign. The variant received -11 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant X-120455421-A-G is Benign according to our data. Variant chrX-120455421-A-G is described in ClinVar as Likely_benign. ClinVar VariationId is 44425.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.654 with no splicing effect.

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.333T>C	p.Ile111Ile	synonymous	Exon 3 of 9	NP_002285.1	P13473-1
	LAMP2	NM_001122606.1		c.333T>C	p.Ile111Ile	synonymous	Exon 3 of 9	NP_001116078.1	P13473-3
	LAMP2	NM_013995.2		c.333T>C	p.Ile111Ile	synonymous	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.333T>C	p.Ile111Ile	synonymous	Exon 3 of 9	ENSP00000200639.4	P13473-1
	LAMP2	ENST00000434600.6	TSL:1	c.333T>C	p.Ile111Ile	synonymous	Exon 3 of 9	ENSP00000408411.2	P13473-3
	LAMP2	ENST00000371335.4	TSL:1	c.333T>C	p.Ile111Ile	synonymous	Exon 3 of 9	ENSP00000360386.4	P13473-2

Frequencies

GnomAD3 genomes Cov.: 20

GnomAD4 exome AF: 0.00000364 AC: 4 AN: 1097456 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 362822

African (AFR) AF: 0.00 AC: 0 AN: 26386

American (AMR) AF: 0.00 AC: 0 AN: 35207

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 30200

South Asian (SAS) AF: 0.00 AC: 0 AN: 54136

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

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4136

European-Non Finnish (NFE) AF: 0.00000357 AC: 3 AN: 841416

Other (OTH) AF: 0.0000217 AC: 1 AN: 46063

GnomAD4 genome Cov.: 20

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	7.0
DANN	Benign	0.70
PhyloP100		-0.65
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs397516742; hg19: chrX-119589276;