18-23532242-C-T

Position:

chr18-23532242-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000271.5(NPC1):c.3797G>A(p.Arg1266Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0497 in 1,614,046 control chromosomes in the GnomAD database, including 4,326 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1266H) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.10 ( 1375 hom., cov: 32)

Exomes 𝑓: 0.044 ( 2951 hom. )

Consequence

NPC1
NM_000271.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:12O:1

Conservation

PhyloP100: 2.23

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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0023930073).

BP6

Variant 18-23532242-C-T is Benign according to our data. Variant chr18-23532242-C-T is described in ClinVar as [Benign]. Clinvar id is 21140.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr18-23532242-C-T is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.232 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.3797G>A	p.Arg1266Gln	missense_variant	25/25	ENST00000269228.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NPC1	ENST00000269228.10 linkuse as main transcript	c.3797G>A	p.Arg1266Gln	missense_variant	25/25	1	NM_000271.5	P1	O15118-1

Frequencies

GnomAD3 genomes

AF:

0.101

AC:

15335

AN:

152048

Hom.:

1373

Cov.:

show subpopulations

Gnomad AFR

AF:

0.236

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.108

Gnomad ASJ

AF:

0.0305

Gnomad EAS

AF:

0.196

Gnomad SAS

AF:

0.0788

Gnomad FIN

AF:

0.00943

Gnomad MID

AF:

0.0538

Gnomad NFE

AF:

0.0310

Gnomad OTH

AF:

0.104

GnomAD3 exomes

AF:

0.0723

AC:

18192

AN:

251450

Hom.:

1320

AF XY:

0.0663

AC XY:

9007

AN XY:

135914

show subpopulations

Gnomad AFR exome

AF:

0.246

Gnomad AMR exome

AF:

0.112

Gnomad ASJ exome

AF:

0.0258

Gnomad EAS exome

AF:

0.206

Gnomad SAS exome

AF:

0.0683

Gnomad FIN exome

AF:

0.0112

Gnomad NFE exome

AF:

0.0312

Gnomad OTH exome

AF:

0.0625

GnomAD4 exome

AF:

0.0443

AC:

64795

AN:

1461880

Hom.:

2951

Cov.:

AF XY:

0.0441

AC XY:

32094

AN XY:

727242

show subpopulations

Gnomad4 AFR exome

AF:

0.247

Gnomad4 AMR exome

AF:

0.111

Gnomad4 ASJ exome

AF:

0.0248

Gnomad4 EAS exome

AF:

0.179

Gnomad4 SAS exome

AF:

0.0679

Gnomad4 FIN exome

AF:

0.0111

Gnomad4 NFE exome

AF:

0.0299

Gnomad4 OTH exome

AF:

0.0596

GnomAD4 genome

AF:

0.101

AC:

15379

AN:

152166

Hom.:

1375

Cov.:

AF XY:

0.103

AC XY:

7627

AN XY:

74396

show subpopulations

Gnomad4 AFR

AF:

0.236

Gnomad4 AMR

AF:

0.108

Gnomad4 ASJ

AF:

0.0305

Gnomad4 EAS

AF:

0.196

Gnomad4 SAS

AF:

0.0789

Gnomad4 FIN

AF:

0.00943

Gnomad4 NFE

AF:

0.0310

Gnomad4 OTH

AF:

0.104

Alfa

AF:

0.0448

Hom.:

620

Bravo

AF:

0.117

TwinsUK

AF:

0.0291

AC:

108

ALSPAC

AF:

0.0317

AC:

122

ESP6500AA

AF:

0.231

AC:

1017

ESP6500EA

AF:

0.0300

AC:

258

ExAC

AF:

0.0731

AC:

8872

Asia WGS

AF:

0.126

AC:

437

AN:

3478

EpiCase

AF:

0.0353

EpiControl

AF:

0.0372

ClinVar

Significance: Benign

Submissions summary: Benign:12Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Niemann-Pick disease, type C1

Benign:6Other:1

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jun 10, 2021	- -
not provided, no classification provided	literature only	GeneReviews	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	Apr 22, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	May 31, 2017	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Nov 21, 2019	- -
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. -

not specified

Benign:4

Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 24, 2015	- -

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Dec 16, 2015	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.076

BayesDel_addAF

Benign

-0.62

BayesDel_noAF

Benign

-0.51

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.25

Eigen

Benign

-0.55

Eigen_PC

Benign

-0.50

FATHMM_MKL

Uncertain

0.93

LIST_S2

Benign

0.80

MetaRNN

Benign

0.0024

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.6

MutationTaster

Benign

0.0012

P;P

PrimateAI

Benign

0.29

PROVEAN

Benign

-0.22

REVEL

Benign

0.18

Sift

Benign

0.31

Sift4G

Benign

0.33

Polyphen

0.0030

Vest4

0.028

MPC

0.30

ClinPred

0.0079

GERP RS

3.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.060

gMVP

0.44

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.050

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