18-23582324-C-T

Position:

• chr18-23582324-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000269228.10(NPC1):​c.57+3963G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.701 in 152,064 control chromosomes in the GnomAD database, including 37,681 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.70 (37681 hom., cov: 32)
• Consequence: NPC1 ENST00000269228.10 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.456

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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.99).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.91 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NPC1	NM_000271.5	c.57+3963G>A		intron_variant		ENST00000269228.10	NP_000262.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NPC1	ENST00000269228.10	c.57+3963G>A		intron_variant		1	NM_000271.5	ENSP00000269228	P1
NPC1	ENST00000540608.5	n.201+3963G>A		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes AF: 0.701 AC: 106569 AN: 151946 Hom.: 37655 Cov.: 32

Gnomad AFR AF: 0.728

Gnomad AMI AF: 0.722

Gnomad AMR AF: 0.756

Gnomad ASJ AF: 0.595

Gnomad EAS AF: 0.932

Gnomad SAS AF: 0.758

Gnomad FIN AF: 0.671

Gnomad MID AF: 0.627

Gnomad NFE AF: 0.663

Gnomad OTH AF: 0.671

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.701 AC: 106659 AN: 152064 Hom.: 37681 Cov.: 32 AF XY: 0.706 AC XY: 52436 AN XY: 74322

Gnomad4 AFR AF: 0.728

Gnomad4 AMR AF: 0.756

Gnomad4 ASJ AF: 0.595

Gnomad4 EAS AF: 0.932

Gnomad4 SAS AF: 0.758

Gnomad4 FIN AF: 0.671

Gnomad4 NFE AF: 0.663

Gnomad4 OTH AF: 0.671

Alfa AF: 0.661 Hom.: 40051

Bravo AF: 0.710

Asia WGS AF: 0.831 AC: 2890 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.99
CADD	Benign	1.1
DANN	Benign	0.67

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

Other links and lift over

dbSNP: rs1429934; hg19: chr18-21162288;