18-23544943-ACC-ACCCC

Position:

• chr18-23544943-ACC-ACCCC

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP6_Moderate BA1

The NM_000271.5(NPC1):​c.1947+15_1947+16dupGG variant causes a intron change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.022 (341 hom., cov: 0)
  • Exomes 𝑓: 0.047 (1638 hom.)
• Consequence: NPC1 NM_000271.5 intron
• Clinical Significance: Benign criteria provided, single submitter B:7
• 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 -10 ACMG points.

• BP6: Variant 18-23544943-A-ACC is Benign according to our data. Variant chr18-23544943-A-ACC is described in ClinVar as [Benign]. Clinvar id is 518276.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr18-23544943-A-ACC is described in Lovd as [Likely_benign]. Variant chr18-23544943-A-ACC is described in Lovd as [Benign].
• BA1: GnomAdExome4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.134 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NPC1	NM_000271.5	c.1947+15_1947+16dupGG		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+17insGG		intron_variant		1	NM_000271.5	ENSP00000269228.4
NPC1	ENST00000591051.1	c.1023+16_1023+17insGG		intron_variant		2		ENSP00000467636.1
NPC1	ENST00000540608.5	n.1861+16_1861+17insGG		intron_variant		2

Frequencies

GnomAD3 genomes AF: 0.0222 AC: 2320 AN: 104638 Hom.: 342 Cov.: 0

Gnomad AFR AF: 0.0264

Gnomad AMI AF: 0.00313

Gnomad AMR AF: 0.0194

Gnomad ASJ AF: 0.0382

Gnomad EAS AF: 0.00883

Gnomad SAS AF: 0.0233

Gnomad FIN AF: 0.0115

Gnomad MID AF: 0.0212

Gnomad NFE AF: 0.0214

Gnomad OTH AF: 0.0174

GnomAD4 exome AF: 0.0465 AC: 41714 AN: 896124 Hom.: 1638 Cov.: 19 AF XY: 0.0481 AC XY: 21978 AN XY: 457298

Gnomad4 AFR exome AF: 0.108

Gnomad4 AMR exome AF: 0.138

Gnomad4 ASJ exome AF: 0.0365

Gnomad4 EAS exome AF: 0.123

Gnomad4 SAS exome AF: 0.0706

Gnomad4 FIN exome AF: 0.0460

Gnomad4 NFE exome AF: 0.0346

Gnomad4 OTH exome AF: 0.0472

GnomAD4 genome AF: 0.0221 AC: 2318 AN: 104682 Hom.: 341 Cov.: 0 AF XY: 0.0226 AC XY: 1123 AN XY: 49586

Gnomad4 AFR AF: 0.0264

Gnomad4 AMR AF: 0.0194

Gnomad4 ASJ AF: 0.0382

Gnomad4 EAS AF: 0.00886

Gnomad4 SAS AF: 0.0228

Gnomad4 FIN AF: 0.0115

Gnomad4 NFE AF: 0.0214

Gnomad4 OTH AF: 0.0173

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, single submitter

Submissions by phenotype

Niemann-Pick disease, type C1 Benign:3

Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	Jul 21, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

not provided Benign:2

Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

not specified Benign:1

Benign, no assertion criteria provided

clinical testing

Genome Diagnostics Laboratory, Amsterdam University Medical Center

-

- -

NPC1-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 12, 2024

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

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;