rs201030806

Variant names:

• chrX-120447991-C-T
• rs201030806
• NM_002294.3:c.591G>A

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Strong BP6 BP7 BS2

The ENST00000200639.9(LAMP2):​c.591G>A​(p.Val197Val) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000213 in 1,208,543 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 98 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00014 (0 hom., 4 hem., cov: 22)
  • Exomes 𝑓: 0.00022 (0 hom. 94 hem.)
• Consequence: LAMP2 ENST00000200639.9 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:11
• Conservation: PhyloP100: -1.76
• Publications: 3 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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant X-120447991-C-T is Benign according to our data. Variant chrX-120447991-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 44433.
• BP7: Synonymous conserved (PhyloP=-1.76 with no splicing effect.
• BS2: High Hemizygotes in GnomAd4 at 4 XL gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000200639.9. 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.591G>A	p.Val197Val	synonymous	Exon 5 of 9	NP_002285.1
	LAMP2	NM_001122606.1		c.591G>A	p.Val197Val	synonymous	Exon 5 of 9	NP_001116078.1
	LAMP2	NM_013995.2		c.591G>A	p.Val197Val	synonymous	Exon 5 of 9	NP_054701.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LAMP2	ENST00000200639.9	TSL:1 MANE Select	c.591G>A	p.Val197Val	synonymous	Exon 5 of 9	ENSP00000200639.4
	LAMP2	ENST00000434600.6	TSL:1	c.591G>A	p.Val197Val	synonymous	Exon 5 of 9	ENSP00000408411.2
	LAMP2	ENST00000371335.4	TSL:1	c.591G>A	p.Val197Val	synonymous	Exon 5 of 9	ENSP00000360386.4

Frequencies

GnomAD3 genomes AF: 0.000135 AC: 15 AN: 110801 Hom.: 0 Cov.: 22

Gnomad AFR AF: 0.0000329

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000193

Gnomad ASJ AF: 0.00114

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00424

Gnomad NFE AF: 0.000151

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000251 AC: 46 AN: 183472 AF XY: 0.000206

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000146

Gnomad ASJ exome AF: 0.00200

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000256

Gnomad OTH exome AF: 0.000221

GnomAD4 exome AF: 0.000221 AC: 243 AN: 1097693 Hom.: 0 Cov.: 30 AF XY: 0.000259 AC XY: 94 AN XY: 363053

African (AFR) AF: 0.0000379 AC: 1 AN: 26385

American (AMR) AF: 0.000114 AC: 4 AN: 35206

Ashkenazi Jewish (ASJ) AF: 0.00155 AC: 30 AN: 19380

East Asian (EAS) AF: 0.00 AC: 0 AN: 30198

South Asian (SAS) AF: 0.000296 AC: 16 AN: 54135

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40523

Middle Eastern (MID) AF: 0.00460 AC: 19 AN: 4133

European-Non Finnish (NFE) AF: 0.000177 AC: 149 AN: 841653

Other (OTH) AF: 0.000521 AC: 24 AN: 46080

GnomAD4 genome AF: 0.000135 AC: 15 AN: 110850 Hom.: 0 Cov.: 22 AF XY: 0.000121 AC XY: 4 AN XY: 33114

African (AFR) AF: 0.0000329 AC: 1 AN: 30430

American (AMR) AF: 0.000192 AC: 2 AN: 10393

Ashkenazi Jewish (ASJ) AF: 0.00114 AC: 3 AN: 2638

East Asian (EAS) AF: 0.00 AC: 0 AN: 3530

South Asian (SAS) AF: 0.00 AC: 0 AN: 2637

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5849

Middle Eastern (MID) AF: 0.00465 AC: 1 AN: 215

European-Non Finnish (NFE) AF: 0.000151 AC: 8 AN: 52973

Other (OTH) AF: 0.00 AC: 0 AN: 1502

Alfa AF: 0.000231 Hom.: 3

Bravo AF: 0.000162

EpiCase AF: 0.000382

EpiControl AF: 0.000296

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	3	Danon disease (3)
-	-	2	not provided (2)
-	-	1	Cardiovascular phenotype (1)
-	1	-	Hypertrophic cardiomyopathy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	1.4
DANN	Benign	0.53
PhyloP100		-1.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs201030806; hg19: chrX-119581846;