18-23532242-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 1P and 20B. PP2BP4_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. 15/21 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. R1266L) 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:13O:1

Conservation

PhyloP100: 2.23

Publications

33 publications found

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 Gene-Disease associations (from GenCC):

Niemann-Pick disease, type C1
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: ClinGen, Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), G2P, Genomics England PanelApp, Myriad Women’s Health
Niemann-Pick disease type C, adult neurologic onset
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
Niemann-Pick disease type C, juvenile neurologic onset
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
Niemann-Pick disease type C, late infantile neurologic onset
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
Niemann-Pick disease type C, severe early infantile neurologic onset
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
Niemann-Pick disease type C, severe perinatal form
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

NPC1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -19 ACMG points.

PP2

Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 171 curated pathogenic missense variants (we use a threshold of 10). The gene has 18 curated benign missense variants. Gene score misZ: 1.0917 (below the threshold of 3.09). Trascript score misZ: 1.706 (below the threshold of 3.09). GenCC associations: The gene is linked to Niemann-Pick disease, type C1, Niemann-Pick disease type C, severe early infantile neurologic onset, Niemann-Pick disease type C, late infantile neurologic onset, Niemann-Pick disease type C, adult neurologic onset, Niemann-Pick disease type C, juvenile neurologic onset, Niemann-Pick disease type C, severe perinatal form.

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 CliVar 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 CliVar 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 CliVar 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 CliVar 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 CliVar 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 CliVar 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 CliVar 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 CliVar 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 CliVar 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 CliVar 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 CliVar 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 CliVar 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 CliVar 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 CliVar 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 CliVar 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 CliVar 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 CliVar 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 CliVar 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 CliVar 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 CliVar 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 CliVar as Benign. Clinvar id is 21140.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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 rank	MANE	Protein	UniProt
NPC1	NM_000271.5 link	c.3797G>A	p.Arg1266Gln	missense_variant	Exon 25 of 25	ENST00000269228.10	NP_000262.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NPC1	ENST00000269228.10 link	c.3797G>A	p.Arg1266Gln	missense_variant	Exon 25 of 25	1	NM_000271.5	ENSP00000269228.4		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

GnomAD2 exomes

AF:

0.0723

AC:

18192

AN:

251450

AF XY:

0.0663

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 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

African (AFR)

AF:

0.247

AC:

8268

AN:

33480

American (AMR)

AF:

0.111

AC:

4947

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0248

AC:

648

AN:

26136

East Asian (EAS)

AF:

0.179

AC:

7103

AN:

39700

South Asian (SAS)

AF:

0.0679

AC:

5857

AN:

86258

European-Finnish (FIN)

AF:

0.0111

AC:

595

AN:

53420

Middle Eastern (MID)

AF:

0.0850

AC:

490

AN:

5768

European-Non Finnish (NFE)

AF:

0.0299

AC:

33285

AN:

1111998

Other (OTH)

AF:

0.0596

AC:

3602

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.472

Heterozygous variant carriers

3920

7839

11759

15678

19598

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1524

3048

4572

6096

7620

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.101

AC:

15379

AN:

152166

Hom.:

1375

Cov.:

AF XY:

0.103

AC XY:

7627

AN XY:

74396

show subpopulations

African (AFR)

AF:

0.236

AC:

9795

AN:

41500

American (AMR)

AF:

0.108

AC:

1647

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.0305

AC:

106

AN:

3472

East Asian (EAS)

AF:

0.196

AC:

1008

AN:

5156

South Asian (SAS)

AF:

0.0789

AC:

380

AN:

4816

European-Finnish (FIN)

AF:

0.00943

AC:

100

AN:

10602

Middle Eastern (MID)

AF:

0.0544

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0310

AC:

2108

AN:

68014

Other (OTH)

AF:

0.104

AC:

219

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

641

1283

1924

2566

3207

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

158

316

474

632

790

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0541

Hom.:

2035

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:13Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Niemann-Pick disease, type C1

Benign:6Other:1

Nov 21, 2019

Natera, Inc.

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

GeneReviews

Significance:not provided

Review Status:no classification provided

Collection Method:literature only

- -

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jun 10, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 31, 2017

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 22, 2016

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not specified

Benign:4

Jul 24, 2015

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not provided

Benign:3

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Mar 03, 2015

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Dec 16, 2015

Mayo Clinic Laboratories, Mayo Clinic

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

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

(source)

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

PhyloP100

2.2

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

Mutation Taster

=93/7

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over