rs375341409

Variant names:

• chrX-120441899-A-G
• rs375341409
• NM_002294.3:c.929-5T>C

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_001122606.1(LAMP2):​c.929-5T>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000282 in 1,203,928 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 13 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.000072 (0 hom., 3 hem., cov: 23)
  • Exomes 𝑓: 0.000024 (0 hom. 10 hem.)
• Consequence: LAMP2 NM_001122606.1 splice_region, intron
• Scores: Splicing: ADA: 0.002729
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts U:1 B:7
• Conservation: PhyloP100: 1.57
• 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: ClinGen, G2P, Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Orphanet

ACMG classification

Our verdict: Benign. The variant received -16 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.75).
• BP6: Variant X-120441899-A-G is Benign according to our data. Variant chrX-120441899-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 180397.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Hemizygotes in GnomAd4 at 3 XL gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001122606.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LAMP2	NM_002294.3	MANE Select	c.929-5T>C		splice_region intron	N/A	NP_002285.1
	LAMP2	NM_001122606.1		c.929-5T>C		splice_region intron	N/A	NP_001116078.1
	LAMP2	NM_013995.2		c.929-5T>C		splice_region intron	N/A	NP_054701.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LAMP2	ENST00000200639.9	TSL:1 MANE Select	c.929-5T>C		splice_region intron	N/A	ENSP00000200639.4
	LAMP2	ENST00000434600.6	TSL:1	c.929-5T>C		splice_region intron	N/A	ENSP00000408411.2
	LAMP2	ENST00000371335.4	TSL:1	c.929-5T>C		splice_region intron	N/A	ENSP00000360386.4

Frequencies

GnomAD3 genomes AF: 0.0000716 AC: 8 AN: 111763 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000150

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000600 AC: 11 AN: 183217 AF XY: 0.000103

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000135

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000238 AC: 26 AN: 1092165 Hom.: 0 Cov.: 28 AF XY: 0.0000280 AC XY: 10 AN XY: 357611

African (AFR) AF: 0.00 AC: 0 AN: 26307

American (AMR) AF: 0.00 AC: 0 AN: 35186

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19331

East Asian (EAS) AF: 0.00 AC: 0 AN: 30170

South Asian (SAS) AF: 0.00 AC: 0 AN: 53986

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40487

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4122

European-Non Finnish (NFE) AF: 0.0000287 AC: 24 AN: 836683

Other (OTH) AF: 0.0000436 AC: 2 AN: 45893

GnomAD4 genome AF: 0.0000716 AC: 8 AN: 111763 Hom.: 0 Cov.: 23 AF XY: 0.0000884 AC XY: 3 AN XY: 33921

African (AFR) AF: 0.00 AC: 0 AN: 30694

American (AMR) AF: 0.00 AC: 0 AN: 10507

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2645

East Asian (EAS) AF: 0.00 AC: 0 AN: 3570

South Asian (SAS) AF: 0.00 AC: 0 AN: 2717

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6042

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 239

European-Non Finnish (NFE) AF: 0.000150 AC: 8 AN: 53165

Other (OTH) AF: 0.00 AC: 0 AN: 1497

Alfa AF: 0.000167 Hom.: 2

Bravo AF: 0.0000907

EpiCase AF: 0.000164

EpiControl AF: 0.00

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	2	Danon disease (2)
-	-	1	not specified (1)
-	1	-	Trifascicular block on electrocardiogram (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.75
CADD	Benign	9.3
DANN	Benign	0.67
PhyloP100		1.6
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0027
dbscSNV1_RF	Benign	0.032
SpliceAI score (max)		0.030		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: rs375341409; hg19: chrX-119575754;