chr18-23544981-C-G

Variant names:

Variant summary

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

The NM_000271.5(NPC1):c.1926G>C(p.Met642Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.687 in 1,530,962 control chromosomes in the GnomAD database, including 374,159 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 nucleotide change resulting in the same amino acid substitution has been previously reported as Benign in Lovd.

Frequency

Genomes: 𝑓 0.74 ( 40038 hom., cov: 22)

Exomes 𝑓: 0.68 ( 334121 hom. )

Consequence

NPC1
NM_000271.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:17

Conservation

PhyloP100: 2.90

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 domain SSD (size 165) in uniprot entity NPC1_HUMAN there are 26 pathogenic changes around while only 4 benign (87%) in NM_000271.5

BP4

Computational evidence support a benign effect (MetaRNN=1.0263868E-6).

BP6

Variant 18-23544981-C-G is Benign according to our data. Variant chr18-23544981-C-G is described in ClinVar as [Benign]. Clinvar id is 92701.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr18-23544981-C-G is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.901 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NPC1	NM_000271.5 link	c.1926G>C	p.Met642Ile	missense_variant	Exon 12 of 25	ENST00000269228.10	NP_000262.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
NPC1	ENST00000269228.10 link	c.1926G>C	p.Met642Ile	missense_variant	Exon 12 of 25	1	NM_000271.5	ENSP00000269228.4	O15118-1
NPC1	ENST00000591051.1 link	c.1002G>C	p.Met334Ile	missense_variant	Exon 5 of 18	2		ENSP00000467636.1	K7EQ23
NPC1	ENST00000540608.5 link	n.1840G>C		non_coding_transcript_exon_variant	Exon 10 of 16	2

Frequencies

GnomAD3 genomes

AF:

0.740

AC:

104617

AN:

141462

Hom.:

39989

Cov.:

show subpopulations

Gnomad AFR

AF:

0.909

Gnomad AMI

AF:

0.719

Gnomad AMR

AF:

0.744

Gnomad ASJ

AF:

0.579

Gnomad EAS

AF:

0.923

Gnomad SAS

AF:

0.761

Gnomad FIN

AF:

0.604

Gnomad MID

AF:

0.644

Gnomad NFE

AF:

0.650

Gnomad OTH

AF:

0.698

GnomAD3 exomes

AF:

0.729

AC:

174136

AN:

238838

Hom.:

66404

AF XY:

0.720

AC XY:

93040

AN XY:

129148

show subpopulations

Gnomad AFR exome

AF:

0.924

Gnomad AMR exome

AF:

0.828

Gnomad ASJ exome

AF:

0.578

Gnomad EAS exome

AF:

0.935

Gnomad SAS exome

AF:

0.768

Gnomad FIN exome

AF:

0.659

Gnomad NFE exome

AF:

0.653

Gnomad OTH exome

AF:

0.693

GnomAD4 exome

AF:

0.682

AC:

947164

AN:

1389384

Hom.:

334121

Cov.:

AF XY:

0.682

AC XY:

470282

AN XY:

689718

show subpopulations

Gnomad4 AFR exome

AF:

0.921

Gnomad4 AMR exome

AF:

0.821

Gnomad4 ASJ exome

AF:

0.575

Gnomad4 EAS exome

AF:

0.944

Gnomad4 SAS exome

AF:

0.768

Gnomad4 FIN exome

AF:

0.660

Gnomad4 NFE exome

AF:

0.655

Gnomad4 OTH exome

AF:

0.694

GnomAD4 genome

AF:

0.740

AC:

104728

AN:

141578

Hom.:

40038

Cov.:

AF XY:

0.739

AC XY:

50240

AN XY:

67968

show subpopulations

Gnomad4 AFR

AF:

0.909

Gnomad4 AMR

AF:

0.744

Gnomad4 ASJ

AF:

0.579

Gnomad4 EAS

AF:

0.922

Gnomad4 SAS

AF:

0.760

Gnomad4 FIN

AF:

0.604

Gnomad4 NFE

AF:

0.650

Gnomad4 OTH

AF:

0.701

Alfa

AF:

0.659

Hom.:

22488

Bravo

AF:

0.763

TwinsUK

AF:

0.655

AC:

2427

ALSPAC

AF:

0.645

AC:

2484

ESP6500AA

AF:

0.910

AC:

4008

ESP6500EA

AF:

0.645

AC:

5547

ExAC

AF:

0.718

AC:

87148

Asia WGS

AF:

0.844

AC:

2934

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:17

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Niemann-Pick disease, type C1

Benign:8

Jun 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 12, 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. -

Sep 16, 2020

Natera, Inc.

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Aug 11, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 28, 2019

Mendelics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

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

- -

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified

Benign:6

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 28, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 -

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

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Nov 21, 2017

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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. -

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

This variant is associated with the following publications: (PMID: 23153210) -

Oct 23, 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

0.079

BayesDel_addAF

Benign

-0.47

BayesDel_noAF

Benign

-0.31

CADD

Benign

DANN

Benign

0.77

DEOGEN2

Benign

0.24

Eigen

Benign

-0.69

Eigen_PC

Benign

-0.36

FATHMM_MKL

Benign

0.22

LIST_S2

Benign

0.29

MetaRNN

Benign

0.0000010

MetaSVM

Benign

-0.94

MutationAssessor

Benign

-2.1

PrimateAI

Uncertain

0.54

PROVEAN

Benign

1.6

REVEL

Benign

0.26

Sift

Benign

1.0

Sift4G

Benign

1.0

Polyphen

0.0

Vest4

0.10

MutPred

0.24

Gain of MoRF binding (P = 0.1764);

MPC

0.28

ClinPred

0.0077

GERP RS

5.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.15

gMVP

0.19

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

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