18-23540480-T-C

Position:

chr18-23540480-T-C

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1BP4_StrongBP6_Very_StrongBA1

The NM_000271.5(NPC1):c.2572A>G(p.Ile858Val) variant causes a missense change. The variant allele was found at a frequency of 0.487 in 1,607,602 control chromosomes in the GnomAD database, including 193,451 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.47 ( 16781 hom., cov: 31)

Exomes 𝑓: 0.49 ( 176670 hom. )

Consequence

NPC1
NM_000271.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:15O:1

Conservation

PhyloP100: 4.93

Variant links:

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]

NPC1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -18 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 5 uncertain in NM_000271.5

BP4

Computational evidence support a benign effect (MetaRNN=7.40361E-5).

BP6

Variant 18-23540480-T-C is Benign according to our data. Variant chr18-23540480-T-C is described in ClinVar as [Benign]. Clinvar id is 21135.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr18-23540480-T-C is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.612 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NPC1	NM_000271.5 linkuse as main transcript	c.2572A>G	p.Ile858Val	missense_variant	17/25	ENST00000269228.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NPC1	ENST00000269228.10 linkuse as main transcript	c.2572A>G	p.Ile858Val	missense_variant	17/25	1	NM_000271.5	P1	O15118-1
NPC1	ENST00000591051.1 linkuse as main transcript	c.1651A>G	p.Ile551Val	missense_variant	10/18	2
NPC1	ENST00000540608.5 linkuse as main transcript	n.2486A>G		non_coding_transcript_exon_variant	15/16	2
NPC1	ENST00000586718.1 linkuse as main transcript	n.363A>G		non_coding_transcript_exon_variant	2/3	3

Frequencies

GnomAD3 genomes

AF:

0.466

AC:

70363

AN:

151124

Hom.:

16762

Cov.:

show subpopulations

Gnomad AFR

AF:

0.380

Gnomad AMI

AF:

0.425

Gnomad AMR

AF:

0.573

Gnomad ASJ

AF:

0.308

Gnomad EAS

AF:

0.630

Gnomad SAS

AF:

0.492

Gnomad FIN

AF:

0.534

Gnomad MID

AF:

0.304

Gnomad NFE

AF:

0.479

Gnomad OTH

AF:

0.444

GnomAD3 exomes

AF:

0.499

AC:

125161

AN:

250608

Hom.:

32488

AF XY:

0.493

AC XY:

66822

AN XY:

135486

show subpopulations

Gnomad AFR exome

AF:

0.378

Gnomad AMR exome

AF:

0.654

Gnomad ASJ exome

AF:

0.307

Gnomad EAS exome

AF:

0.624

Gnomad SAS exome

AF:

0.490

Gnomad FIN exome

AF:

0.503

Gnomad NFE exome

AF:

0.470

Gnomad OTH exome

AF:

0.467

GnomAD4 exome

AF:

0.489

AC:

711784

AN:

1456382

Hom.:

176670

Cov.:

AF XY:

0.487

AC XY:

352658

AN XY:

724846

show subpopulations

Gnomad4 AFR exome

AF:

0.369

Gnomad4 AMR exome

AF:

0.645

Gnomad4 ASJ exome

AF:

0.303

Gnomad4 EAS exome

AF:

0.657

Gnomad4 SAS exome

AF:

0.493

Gnomad4 FIN exome

AF:

0.498

Gnomad4 NFE exome

AF:

0.485

Gnomad4 OTH exome

AF:

0.469

GnomAD4 genome

AF:

0.466

AC:

70442

AN:

151220

Hom.:

16781

Cov.:

AF XY:

0.470

AC XY:

34739

AN XY:

73838

show subpopulations

Gnomad4 AFR

AF:

0.380

Gnomad4 AMR

AF:

0.574

Gnomad4 ASJ

AF:

0.308

Gnomad4 EAS

AF:

0.630

Gnomad4 SAS

AF:

0.493

Gnomad4 FIN

AF:

0.534

Gnomad4 NFE

AF:

0.479

Gnomad4 OTH

AF:

0.449

Alfa

AF:

0.464

Hom.:

33404

Bravo

AF:

0.467

TwinsUK

AF:

0.494

AC:

1833

ALSPAC

AF:

0.496

AC:

1911

ESP6500AA

AF:

0.388

AC:

1711

ESP6500EA

AF:

0.471

AC:

4047

ExAC

AF:

0.490

AC:

59504

Asia WGS

AF:

0.549

AC:

1908

AN:

3478

EpiCase

AF:

0.456

EpiControl

AF:

0.445

ClinVar

Significance: Benign

Submissions summary: Benign:15Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Niemann-Pick disease, type C1

Benign:7Other:1

Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	Apr 22, 2016	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
not provided, no classification provided	literature only	GeneReviews	-	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jun 10, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	Sep 21, 2015	- -

not specified

Benign:6

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 28, 2016	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 24, 2015	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

not provided

Benign:2

Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Oct 20, 2015	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.059

BayesDel_addAF

Benign

-0.34

BayesDel_noAF

Benign

-0.12

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.29

Eigen

Benign

-0.054

Eigen_PC

Benign

0.17

FATHMM_MKL

Uncertain

0.95

LIST_S2

Benign

0.69

MetaRNN

Benign

0.000074

MetaSVM

Benign

-0.95

MutationAssessor

Benign

1.3

MutationTaster

Benign

7.5e-10

P;P

PrimateAI

Benign

0.39

PROVEAN

Benign

-0.72

REVEL

Uncertain

0.33

Sift

Benign

0.23

Sift4G

Benign

0.28

Polyphen

0.047

Vest4

0.075

MPC

0.22

ClinPred

0.0081

GERP RS

6.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.28

gMVP

0.39

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.10

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over