X-120426652-G-A

Variant names:

• chrX-120426652-G-A
• rs1045953
• NM_002294.3:c.*4671C>T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_002294.3(LAMP2):​c.*4671C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.091 in 111,271 control chromosomes in the GnomAD database, including 1,115 homozygotes. There are 2,755 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency: Genomes: 𝑓 0.091 (1115 hom., 2755 hem., cov: 21)
• Consequence: LAMP2 NM_002294.3 3_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, single submitter B:2
• Conservation: PhyloP100: 0.741
• Publications: 1 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant X-120426652-G-A is Benign according to our data. Variant chrX-120426652-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 367742.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.303 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LAMP2	NM_002294.3	c.*4671C>T		3_prime_UTR_variant	Exon 9 of 9	ENST00000200639.9	NP_002285.1
LAMP2	NM_001122606.1	c.*1832C>T		3_prime_UTR_variant	Exon 9 of 9		NP_001116078.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LAMP2	ENST00000200639.9	c.*4671C>T		3_prime_UTR_variant	Exon 9 of 9	1	NM_002294.3	ENSP00000200639.4

Frequencies

GnomAD3 genomes AF: 0.0908 AC: 10102 AN: 111221 Hom.: 1114 Cov.: 21

Gnomad AFR AF: 0.308

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0499

Gnomad ASJ AF: 0.000378

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00186

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0426

Gnomad NFE AF: 0.00149

Gnomad OTH AF: 0.0793

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.0910 AC: 10127 AN: 111271 Hom.: 1115 Cov.: 21 AF XY: 0.0821 AC XY: 2755 AN XY: 33543

African (AFR) AF: 0.309 AC: 9391 AN: 30437

American (AMR) AF: 0.0499 AC: 523 AN: 10485

Ashkenazi Jewish (ASJ) AF: 0.000378 AC: 1 AN: 2644

East Asian (EAS) AF: 0.00 AC: 0 AN: 3581

South Asian (SAS) AF: 0.00187 AC: 5 AN: 2673

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6021

Middle Eastern (MID) AF: 0.0421 AC: 9 AN: 214

European-Non Finnish (NFE) AF: 0.00149 AC: 79 AN: 53016

Other (OTH) AF: 0.0783 AC: 119 AN: 1519

Alfa AF: 0.0678 Hom.: 271

Bravo AF: 0.106

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, single submitter

Submissions by phenotype

Danon disease Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Hypertrophic cardiomyopathy Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	2.5
DANN	Benign	0.54
PhyloP100		0.74

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1045953; hg19: chrX-119560507;