rs138991195

Variant names:

• chrX-120447996-T-A
• rs138991195
• NM_002294.3:c.586A>T

Your query was ambiguous. Multiple possible variants found:

• chrX-120447996-T-A
• chrX-120447996-T-C

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4_Moderate BP6 BS2

The NM_002294.3(LAMP2):​c.586A>T​(p.Thr196Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000399 in 1,208,560 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 160 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). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T196A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00041 (0 hom., 13 hem., cov: 23)
  • Exomes 𝑓: 0.00040 (0 hom. 147 hem.)
• Consequence: LAMP2 NM_002294.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:13
• Conservation: PhyloP100: 1.45
• Publications: 11 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 -7 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.07970959).
• BP6: Variant X-120447996-T-A is Benign according to our data. Variant chrX-120447996-T-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 44432.
• BS2: High Hemizygotes in GnomAd4 at 13 XL gene

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.586A>T	p.Thr196Ser	missense	Exon 5 of 9	NP_002285.1	P13473-1
	LAMP2	NM_001122606.1		c.586A>T	p.Thr196Ser	missense	Exon 5 of 9	NP_001116078.1	P13473-3
	LAMP2	NM_013995.2		c.586A>T	p.Thr196Ser	missense	Exon 5 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.586A>T	p.Thr196Ser	missense	Exon 5 of 9	ENSP00000200639.4	P13473-1
	LAMP2	ENST00000434600.6	TSL:1	c.586A>T	p.Thr196Ser	missense	Exon 5 of 9	ENSP00000408411.2	P13473-3
	LAMP2	ENST00000371335.4	TSL:1	c.586A>T	p.Thr196Ser	missense	Exon 5 of 9	ENSP00000360386.4	P13473-2

Frequencies

GnomAD3 genomes AF: 0.000414 AC: 46 AN: 111131 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.000131

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000288

Gnomad ASJ AF: 0.00114

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000679

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000332 AC: 61 AN: 183475 AF XY: 0.000471

Gnomad AFR exome AF: 0.000228

Gnomad AMR exome AF: 0.0000365

Gnomad ASJ exome AF: 0.000935

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000610

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000397 AC: 436 AN: 1097376 Hom.: 0 Cov.: 30 AF XY: 0.000405 AC XY: 147 AN XY: 362736

African (AFR) AF: 0.0000758 AC: 2 AN: 26380

American (AMR) AF: 0.000114 AC: 4 AN: 35204

Ashkenazi Jewish (ASJ) AF: 0.000981 AC: 19 AN: 19377

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 54125

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40524

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4133

European-Non Finnish (NFE) AF: 0.000481 AC: 405 AN: 841361

Other (OTH) AF: 0.000130 AC: 6 AN: 46072

GnomAD4 genome AF: 0.000414 AC: 46 AN: 111184 Hom.: 0 Cov.: 23 AF XY: 0.000389 AC XY: 13 AN XY: 33404

African (AFR) AF: 0.000131 AC: 4 AN: 30531

American (AMR) AF: 0.000287 AC: 3 AN: 10443

Ashkenazi Jewish (ASJ) AF: 0.00114 AC: 3 AN: 2642

East Asian (EAS) AF: 0.00 AC: 0 AN: 3534

South Asian (SAS) AF: 0.00 AC: 0 AN: 2647

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5930

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 216

European-Non Finnish (NFE) AF: 0.000679 AC: 36 AN: 53044

Other (OTH) AF: 0.00 AC: 0 AN: 1513

Alfa AF: 0.000680 Hom.: 16

Bravo AF: 0.000495

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000692 AC: 2

ESP6500AA AF: 0.000522 AC: 2

ESP6500EA AF: 0.000446 AC: 3

ExAC AF: 0.000272 AC: 33

EpiCase AF: 0.000927

EpiControl AF: 0.00142

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	6	not provided (7)
-	-	3	not specified (3)
-	-	1	Cardiomyopathy (1)
-	-	1	Cardiovascular phenotype (1)
-	-	1	Danon disease (1)
-	-	1	Hypertrophic cardiomyopathy (1)
-	1	-	Intellectual disability (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
CardioboostCm	Benign	0.023
BayesDel_addAF	Benign	-0.48	T
BayesDel_noAF	Benign	-0.57
CADD	Benign	21
DANN	Uncertain	0.98
DEOGEN2	Benign	0.32	T
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Benign	0.62	T
M_CAP	Uncertain	0.18	D
MetaRNN	Benign	0.080	T
MetaSVM	Benign	-0.78	T
MutationAssessor	Uncertain	2.6	M
PhyloP100		1.5
PrimateAI	Benign	0.39	T
PROVEAN	Uncertain	-3.1	D
REVEL	Benign	0.25
Sift	Benign	0.078	T
Sift4G	Benign	0.096	T
Polyphen		0.99	D
Vest4		0.18
MVP		0.59
MPC		0.80
ClinPred		0.10	T
GERP RS		6.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.43
gMVP		0.67
Mutation Taster		=99/1	polymorphism

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: rs138991195; hg19: chrX-119581851;