NM_002294.3:c.927C>T

Variant names:

• chrX-120442600-G-A
• rs73219144
• NM_002294.3:c.927C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_002294.3(LAMP2):​c.927C>T​(p.Ser309Ser) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0342 in 1,203,141 control chromosomes in the GnomAD database, including 591 homozygotes. There are 13,128 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 0.027 (39 hom., 838 hem., cov: 22)
  • Exomes 𝑓: 0.035 (552 hom. 12290 hem.)
• Consequence: LAMP2 NM_002294.3 splice_region, synonymous
• Scores: Splicing: ADA: 0.0004918
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:18
• Conservation: PhyloP100: 0.349
• Publications: 5 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.52).
• BP6: Variant X-120442600-G-A is Benign according to our data. Variant chrX-120442600-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 44445.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.349 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0267 (2983/111660) while in subpopulation NFE AF = 0.0408 (2166/53069). AF 95% confidence interval is 0.0394. There are 39 homozygotes in GnomAd4. There are 838 alleles in the male GnomAd4 subpopulation. Median coverage is 22. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 39 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.927C>T	p.Ser309Ser	splice_region synonymous	Exon 7 of 9	NP_002285.1	P13473-1
	LAMP2	NM_001122606.1		c.927C>T	p.Ser309Ser	splice_region synonymous	Exon 7 of 9	NP_001116078.1	P13473-3
	LAMP2	NM_013995.2		c.927C>T	p.Ser309Ser	splice_region synonymous	Exon 7 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.927C>T	p.Ser309Ser	splice_region synonymous	Exon 7 of 9	ENSP00000200639.4	P13473-1
	LAMP2	ENST00000434600.6	TSL:1	c.927C>T	p.Ser309Ser	splice_region synonymous	Exon 7 of 9	ENSP00000408411.2	P13473-3
	LAMP2	ENST00000371335.4	TSL:1	c.927C>T	p.Ser309Ser	splice_region synonymous	Exon 7 of 9	ENSP00000360386.4	P13473-2

Frequencies

GnomAD3 genomes AF: 0.0268 AC: 2986 AN: 111606 Hom.: 39 Cov.: 22

Gnomad AFR AF: 0.00533

Gnomad AMI AF: 0.0219

Gnomad AMR AF: 0.0254

Gnomad ASJ AF: 0.0284

Gnomad EAS AF: 0.000280

Gnomad SAS AF: 0.00859

Gnomad FIN AF: 0.0383

Gnomad MID AF: 0.0336

Gnomad NFE AF: 0.0408

Gnomad OTH AF: 0.0258

GnomAD2 exomes AF: 0.0270 AC: 4943 AN: 183267 AF XY: 0.0282

Gnomad AFR exome AF: 0.00456

Gnomad AMR exome AF: 0.0160

Gnomad ASJ exome AF: 0.0297

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0389

Gnomad NFE exome AF: 0.0400

Gnomad OTH exome AF: 0.0385

GnomAD4 exome AF: 0.0349 AC: 38118 AN: 1091481 Hom.: 552 Cov.: 28 AF XY: 0.0344 AC XY: 12290 AN XY: 357533

African (AFR) AF: 0.00361 AC: 95 AN: 26301

American (AMR) AF: 0.0163 AC: 573 AN: 35198

Ashkenazi Jewish (ASJ) AF: 0.0304 AC: 588 AN: 19343

East Asian (EAS) AF: 0.0000331 AC: 1 AN: 30175

South Asian (SAS) AF: 0.00922 AC: 498 AN: 54001

European-Finnish (FIN) AF: 0.0394 AC: 1595 AN: 40443

Middle Eastern (MID) AF: 0.0451 AC: 186 AN: 4127

European-Non Finnish (NFE) AF: 0.0396 AC: 33085 AN: 836037

Other (OTH) AF: 0.0326 AC: 1497 AN: 45856

GnomAD4 genome AF: 0.0267 AC: 2983 AN: 111660 Hom.: 39 Cov.: 22 AF XY: 0.0247 AC XY: 838 AN XY: 33870

African (AFR) AF: 0.00532 AC: 164 AN: 30810

American (AMR) AF: 0.0254 AC: 267 AN: 10525

Ashkenazi Jewish (ASJ) AF: 0.0284 AC: 75 AN: 2639

East Asian (EAS) AF: 0.000281 AC: 1 AN: 3560

South Asian (SAS) AF: 0.00824 AC: 22 AN: 2671

European-Finnish (FIN) AF: 0.0383 AC: 228 AN: 5957

Middle Eastern (MID) AF: 0.0276 AC: 6 AN: 217

European-Non Finnish (NFE) AF: 0.0408 AC: 2166 AN: 53069

Other (OTH) AF: 0.0255 AC: 39 AN: 1528

Alfa AF: 0.0346 Hom.: 1657

Bravo AF: 0.0246

EpiCase AF: 0.0439

EpiControl AF: 0.0395

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	8	not specified (8)
-	-	4	Danon disease (4)
-	-	3	not provided (3)
-	-	2	Hypertrophic cardiomyopathy (2)
-	-	1	Cardiovascular phenotype (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.52
CADD	Benign	5.4
DANN	Benign	0.62
PhyloP100		0.35
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=63/37	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00049
dbscSNV1_RF	Benign	0.032
SpliceAI score (max)		0.050		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: rs73219144; hg19: chrX-119576455; COSMIC: COSV52353971;