18-23544943-ACC-ACCCCCCCCCC

Position:

• chr18-23544943-ACC-ACCCCCCCCCC

Variant summary

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

The ENST00000269228.10(NPC1):​c.1947+16_1947+17insGGGGGGGG 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 (180 hom., cov: 0)
  • Exomes 𝑓: 0.0012 (24 hom.)
  • Failed GnomAD Quality Control
• 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 sas. gnomad4_exome allele frequency = 0.00118 (1105/936232) while in subpopulation SAS AF= 0.00327 (234/71478). AF 95% confidence interval is 0.00293. There are 24 homozygotes in gnomad4_exome. There are 616 alleles in male gnomad4_exome subpopulation. Median coverage is 19. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 24 AR gene

Transcripts

RefSeq

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

Frequencies

GnomAD3 genomes AF: 0.00 AC: 2215 AN: 104096 Hom.: 179 Cov.: 0 FAILED QC

Gnomad AFR AF: 0.00861

Gnomad AMI AF: 0.0329

Gnomad AMR AF: 0.0111

Gnomad ASJ AF: 0.0188

Gnomad EAS AF: 0.0175

Gnomad SAS AF: 0.0142

Gnomad FIN AF: 0.00833

Gnomad MID AF: 0.00424

Gnomad NFE AF: 0.0339

Gnomad OTH AF: 0.0174

GnomAD4 exome AF: 0.00118 AC: 1105 AN: 936232 Hom.: 24 Cov.: 19 AF XY: 0.00129 AC XY: 616 AN XY: 478366

Gnomad4 AFR exome AF: 0.000116

Gnomad4 AMR exome AF: 0.00128

Gnomad4 ASJ exome AF: 0.000521

Gnomad4 EAS exome AF: 0.00126

Gnomad4 SAS exome AF: 0.00327

Gnomad4 FIN exome AF: 0.00402

Gnomad4 NFE exome AF: 0.000845

Gnomad4 OTH exome AF: 0.00115

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.0213 AC: 2217 AN: 104142 Hom.: 180 Cov.: 0 AF XY: 0.0174 AC XY: 860 AN XY: 49368

Gnomad4 AFR AF: 0.00865

Gnomad4 AMR AF: 0.0111

Gnomad4 ASJ AF: 0.0188

Gnomad4 EAS AF: 0.0175

Gnomad4 SAS AF: 0.0143

Gnomad4 FIN AF: 0.00833

Gnomad4 NFE AF: 0.0339

Gnomad4 OTH AF: 0.0173

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;