rs1555634618

chr18-23544952-C-CAchr18-23544952-C-CCCCCCGchr18-23544952-C-CCCCCGchr18-23544952-C-CCCCCTchr18-23544952-C-CCCCGchr18-23544952-C-CCCCTchr18-23544952-C-CCCGchr18-23544952-C-CCCGCGchr18-23544952-C-CCGchr18-23544952-C-CCGCCGchr18-23544952-C-CCTCCGchr18-23544952-C-CT

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP6_Moderate

The NM_000271.5(NPC1):c.1947+7_1947+8insT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000777 in 1,287,328 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: not found (cov: 0)
  • Exomes 𝑓: 7.8e-7 (0 hom.)
• Consequence: NPC1 NM_000271.5 splice_region, intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.0320

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP6: Variant 18-23544952-C-CA is Benign according to our data. Variant chr18-23544952-C-CA is described in ClinVar as [Likely_benign]. Clinvar id is 1562291.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NPC1	NM_000271.5	c.1947+7_1947+8insT		splice_region_variant, intron_variant		ENST00000269228.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NPC1	ENST00000269228.10	c.1947+7_1947+8insT		splice_region_variant, intron_variant		1	NM_000271.5	P1
NPC1	ENST00000591051.1	c.1025+7_1025+8insT		splice_region_variant, intron_variant		2
NPC1	ENST00000540608.5	n.1861+7_1861+8insT		splice_region_variant, intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes Cov.: 0

GnomAD4 exome AF: 7.77e-7 AC: 1 AN: 1287328 Hom.: 0 Cov.: 25 AF XY: 0.00 AC XY: 0 AN XY: 647090

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: 0.00000104

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 0

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Niemann-Pick disease, type C1 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Feb 05, 2022

- -

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: chr18-21124916;