18-23544943-ACCCC-ACCCCCCCCCCCCCC

Variant names:

• chr18-23544943-A-ACCCCCCCCCC
• NM_000271.5:c.1947+16_1947+17insGGGGGGGGGG

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS1

The NM_000271.5(NPC1):​c.1947+16_1947+17insGGGGGGGGGG variant causes a intron change involving the alteration of a non-conserved nucleotide. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.021 (252 hom., cov: 0)
  • Exomes 𝑓: 0.00065 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: NPC1 NM_000271.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.952

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 Likely_benign. Variant got -4 ACMG points.

• BS1: Variant frequency is greater than expected in population sas. gnomad4_exome allele frequency = 0.000651 (610/936774) while in subpopulation SAS AF= 0.00166 (119/71574). AF 95% confidence interval is 0.00142. There are 0 homozygotes in gnomad4_exome. There are 304 alleles in male gnomad4_exome subpopulation. Median coverage is 19. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NPC1	NM_000271.5	c.1947+16_1947+17insGGGGGGGGGG		intron_variant	Intron 12 of 24	ENST00000269228.10	NP_000262.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NPC1	ENST00000269228.10	c.1947+16_1947+17insGGGGGGGGGG		intron_variant	Intron 12 of 24	1	NM_000271.5	ENSP00000269228.4
NPC1	ENST00000591051.1	c.1023+16_1023+17insGGGGGGGGGG		intron_variant	Intron 5 of 17	2		ENSP00000467636.1
NPC1	ENST00000540608.5	n.1861+16_1861+17insGGGGGGGGGG		intron_variant	Intron 10 of 15	2

Frequencies

GnomAD3 genomes AF: 0.00 AC: 2194 AN: 103974 Hom.: 252 Cov.: 0 FAILED QC

Gnomad AFR AF: 0.00803

Gnomad AMI AF: 0.0334

Gnomad AMR AF: 0.00809

Gnomad ASJ AF: 0.0245

Gnomad EAS AF: 0.00943

Gnomad SAS AF: 0.0188

Gnomad FIN AF: 0.00934

Gnomad MID AF: 0.00424

Gnomad NFE AF: 0.0343

Gnomad OTH AF: 0.0168

GnomAD4 exome AF: 0.000651 AC: 610 AN: 936774 Hom.: 0 Cov.: 19 AF XY: 0.000635 AC XY: 304 AN XY: 478652

Gnomad4 AFR exome AF: 0.0000771

Gnomad4 AMR exome AF: 0.000791

Gnomad4 ASJ exome AF: 0.000378

Gnomad4 EAS exome AF: 0.00111

Gnomad4 SAS exome AF: 0.00166

Gnomad4 FIN exome AF: 0.000967

Gnomad4 NFE exome AF: 0.000531

Gnomad4 OTH exome AF: 0.000660

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.0211 AC: 2194 AN: 104022 Hom.: 252 Cov.: 0 AF XY: 0.0174 AC XY: 860 AN XY: 49344

Gnomad4 AFR AF: 0.00801

Gnomad4 AMR AF: 0.00809

Gnomad4 ASJ AF: 0.0245

Gnomad4 EAS AF: 0.00946

Gnomad4 SAS AF: 0.0189

Gnomad4 FIN AF: 0.00934

Gnomad4 NFE AF: 0.0343

Gnomad4 OTH AF: 0.0167

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr18-21124907;