18-23544943-ACC-ACCCCCCCCCCC

Position:

• chr18-23544943-ACC-ACCCCCCCCCCC

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BS1 BS2

The ENST00000269228.10(NPC1):​c.1947+16_1947+17insGGGGGGGGG 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 0.0024 (24 hom., cov: 0)
  • Exomes 𝑓: 0.00076 (10 hom.)
• Consequence: NPC1 ENST00000269228.10 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 Benign. Variant got -8 ACMG points.

• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00243 (254/104572) while in subpopulation NFE AF= 0.0033 (157/47592). AF 95% confidence interval is 0.00288. There are 24 homozygotes in gnomad4. There are 105 alleles in male gnomad4 subpopulation. Median coverage is 0. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 24 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NPC1	NM_000271.5	c.1947+16_1947+17insGGGGGGGGG		intron_variant		ENST00000269228.10	NP_000262.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NPC1	ENST00000269228.10	c.1947+16_1947+17insGGGGGGGGG		intron_variant		1	NM_000271.5	ENSP00000269228	P1
NPC1	ENST00000591051.1	c.1025+16_1025+17insGGGGGGGGG		intron_variant		2		ENSP00000467636
NPC1	ENST00000540608.5	n.1861+16_1861+17insGGGGGGGGG		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes AF: 0.00243 AC: 254 AN: 104526 Hom.: 24 Cov.: 0

Gnomad AFR AF: 0.00134

Gnomad AMI AF: 0.00156

Gnomad AMR AF: 0.00246

Gnomad ASJ AF: 0.00178

Gnomad EAS AF: 0.00277

Gnomad SAS AF: 0.00198

Gnomad FIN AF: 0.000810

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00330

Gnomad OTH AF: 0.00486

GnomAD4 exome AF: 0.000764 AC: 716 AN: 936626 Hom.: 10 Cov.: 19 AF XY: 0.000846 AC XY: 405 AN XY: 478558

Gnomad4 AFR exome AF: 0.0000771

Gnomad4 AMR exome AF: 0.00106

Gnomad4 ASJ exome AF: 0.000568

Gnomad4 EAS exome AF: 0.00104

Gnomad4 SAS exome AF: 0.00208

Gnomad4 FIN exome AF: 0.00228

Gnomad4 NFE exome AF: 0.000546

Gnomad4 OTH exome AF: 0.000684

GnomAD4 genome AF: 0.00243 AC: 254 AN: 104572 Hom.: 24 Cov.: 0 AF XY: 0.00212 AC XY: 105 AN XY: 49538

Gnomad4 AFR AF: 0.00134

Gnomad4 AMR AF: 0.00246

Gnomad4 ASJ AF: 0.00178

Gnomad4 EAS AF: 0.00278

Gnomad4 SAS AF: 0.00199

Gnomad4 FIN AF: 0.000810

Gnomad4 NFE AF: 0.00330

Gnomad4 OTH AF: 0.00483

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: rs3837910; hg19: chr18-21124907;