18-23543572-TAAAAAAAAAAA-TAAAAAA

Position:

• chr18-23543572-TAAAAAAAAAAA-TAAAAAA

Variant summary

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

The NM_000271.5(NPC1):​c.2131-8_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 0.000044 in 1,205,326 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: 0.000049 (0 hom.)
• Consequence: NPC1 NM_000271.5 splice_region, splice_polypyrimidine_tract, intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.136

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]

ACMG classification

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	Protein	UniProt
NPC1	NM_000271.5	c.2131-8_2131-4del		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000269228.10	NP_000262.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NPC1	ENST00000269228.10	c.2131-8_2131-4del		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_000271.5	ENSP00000269228	P1
NPC1	ENST00000591051.1	c.1209-8_1209-4del		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		2		ENSP00000467636
NPC1	ENST00000540608.5	n.2045-8_2045-4del		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes AF: 0.00000696 AC: 1 AN: 143578 Hom.: 0 Cov.: 0

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: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000153

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000490 AC: 52 AN: 1061748 Hom.: 0 AF XY: 0.0000534 AC XY: 29 AN XY: 542642

Gnomad4 AFR exome AF: 0.0000420

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.0000888

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000125

Gnomad4 FIN exome AF: 0.0000249

Gnomad4 NFE exome AF: 0.0000449

Gnomad4 OTH exome AF: 0.0000860

GnomAD4 genome AF: 0.00000696 AC: 1 AN: 143578 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 69456

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: 0.00

Gnomad4 NFE AF: 0.0000153

Gnomad4 OTH AF: 0.00

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs11299077; hg19: chr18-21123536;