chr18-23544943-ACCCC-A

Variant names:

• chr18-23544943-ACCCC-A
• NM_000271.5:c.1947+13_1947+16delGGGG

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP6

The NM_000271.5(NPC1):​c.1947+13_1947+16delGGGG variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000533 in 937,566 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in Lovd as Likely benign (no stars).

• Frequency:
  • Genomes: not found (cov: 0)
  • Exomes 𝑓: 0.0000053 (0 hom.)
• Consequence: NPC1 NM_000271.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.765

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP6: Variant 18-23544943-ACCCC-A is Benign according to our data. Variant chr18-23544943-ACCCC-A is described in Lovd as [Likely_benign]. Variant chr18-23544943-ACCCC-A is described in Lovd as [Benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NPC1	NM_000271.5	c.1947+13_1947+16delGGGG		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+13_1947+16delGGGG		intron_variant	Intron 12 of 24	1	NM_000271.5	ENSP00000269228.4
NPC1	ENST00000591051.1	c.1023+13_1023+16delGGGG		intron_variant	Intron 5 of 17	2		ENSP00000467636.1
NPC1	ENST00000540608.5	n.1861+13_1861+16delGGGG		intron_variant	Intron 10 of 15	2

Frequencies

GnomAD3 genomes Cov.: 0

GnomAD4 exome AF: 0.00000533 AC: 5 AN: 937566 Hom.: 0 AF XY: 0.00000417 AC XY: 2 AN XY: 479080

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000747

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr18-21124907;