Variant chr18-23543572-TAAAA-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_000271.5(NPC1):c.2131-7_2131-4del variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000331 in 1,204,202 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.0000070 ( 0 hom., cov: 0)

Exomes 𝑓: 0.00038 ( 0 hom. )

Consequence

NPC1
NM_000271.5 splice_region, splice_polypyrimidine_tract, intron

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.136

Variant links:

Genes affected

NPC1 (HGNC:7897): (NPC intracellular cholesterol transporter 1) This gene encodes a large protein that resides in the limiting membrane of endosomes and lysosomes and mediates intracellular cholesterol trafficking via binding of cholesterol to its N-terminal domain. It is predicted to have a cytoplasmic C-terminus, 13 transmembrane domains, and 3 large loops in the lumen of the endosome - the last loop being at the N-terminus. This protein transports low-density lipoproteins to late endosomal/lysosomal compartments where they are hydrolized and released as free cholesterol. Defects in this gene cause Niemann-Pick type C disease, a rare autosomal recessive neurodegenerative disorder characterized by over accumulation of cholesterol and glycosphingolipids in late endosomal/lysosomal compartments.[provided by RefSeq, Aug 2009]

NPC1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NPC1	NM_000271.5 linkuse as main transcript	c.2131-7_2131-4del		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000269228.10

Ensembl

Gene	Transcript	HGVSc	Effect	TSL	MANE	Appris	UniProt
NPC1	ENST00000269228.10 linkuse as main transcript	c.2131-7_2131-4del	splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant	1	NM_000271.5	P1	O15118-1
NPC1	ENST00000591051.1 linkuse as main transcript	c.1209-7_1209-4del	splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant	2
NPC1	ENST00000540608.5 linkuse as main transcript	n.2045-7_2045-4del	splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant, non_coding_transcript_variant	2

Frequencies

GnomAD3 genomes

AF:

0.00000696

AC:

AN:

143576

Hom.:

Cov.:

show subpopulations

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:

0.000116

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000219

AC:

AN:

173230

Hom.:

AF XY:

0.000199

AC XY:

AN XY:

95426

show subpopulations

Gnomad AFR exome

AF:

0.0000912

Gnomad AMR exome

AF:

0.000369

Gnomad ASJ exome

AF:

0.000131

Gnomad EAS exome

AF:

0.000309

Gnomad SAS exome

AF:

0.000417

Gnomad FIN exome

AF:

0.000190

Gnomad NFE exome

AF:

0.000136

Gnomad OTH exome

AF:

0.000233

GnomAD4 exome

AF:

0.000375

AC:

398

AN:

1060562

Hom.:

AF XY:

0.000321

AC XY:

174

AN XY:

542036

show subpopulations

Gnomad4 AFR exome

AF:

0.000968

Gnomad4 AMR exome

AF:

0.000344

Gnomad4 ASJ exome

AF:

0.000178

Gnomad4 EAS exome

AF:

0.000112

Gnomad4 SAS exome

AF:

0.000307

Gnomad4 FIN exome

AF:

0.0000499

Gnomad4 NFE exome

AF:

0.000406

Gnomad4 OTH exome

AF:

0.000258

GnomAD4 genome

AF:

0.00000696

AC:

AN:

143640

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

69540

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000116

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

LitVar

Other links and lift over