18-23544981-C-G

Variant names:

• chr18-23544981-C-G
• rs1788799
• NM_000271.5:c.1926G>C

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 3P and 20B. PM1 PP2 BP4_Strong BP6_Very_Strong BA1

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. 15/21 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 ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M642T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.74 (40038 hom., cov: 22)
  • Exomes 𝑓: 0.68 (334121 hom.)
• Consequence: NPC1 NM_000271.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:17
• Conservation: PhyloP100: 2.90
• Publications: 73 publications found

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

ACMG classification

Our verdict: Benign. The variant received -17 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 4 uncertain in NM_000271.5
• 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=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 VariationId is 92701.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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	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	Appris	UniProt
NPC1	ENST00000269228.10	c.1926G>C	p.Met642Ile	missense_variant	Exon 12 of 25	1	NM_000271.5	ENSP00000269228.4
NPC1	ENST00000591051.1	c.1002G>C	p.Met334Ile	missense_variant	Exon 5 of 18	2		ENSP00000467636.1
NPC1	ENST00000540608.5	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.: 22

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

GnomAD2 exomes AF: 0.729 AC: 174136 AN: 238838 AF XY: 0.720

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 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.: 33 AF XY: 0.682 AC XY: 470282 AN XY: 689718

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.921 AC: 30440 AN: 33068

American (AMR) AF: 0.821 AC: 34961 AN: 42608

Ashkenazi Jewish (ASJ) AF: 0.575 AC: 14163 AN: 24622

East Asian (EAS) AF: 0.944 AC: 36721 AN: 38914

South Asian (SAS) AF: 0.768 AC: 62468 AN: 81360

European-Finnish (FIN) AF: 0.660 AC: 33153 AN: 50202

Middle Eastern (MID) AF: 0.631 AC: 3514 AN: 5570

European-Non Finnish (NFE) AF: 0.655 AC: 691882 AN: 1055624

Other (OTH) AF: 0.694 AC: 39862 AN: 57416

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.740 AC: 104728 AN: 141578 Hom.: 40038 Cov.: 22 AF XY: 0.739 AC XY: 50240 AN XY: 67968

African (AFR) AF: 0.909 AC: 35552 AN: 39118

American (AMR) AF: 0.744 AC: 9866 AN: 13256

Ashkenazi Jewish (ASJ) AF: 0.579 AC: 1960 AN: 3386

East Asian (EAS) AF: 0.922 AC: 4390 AN: 4762

South Asian (SAS) AF: 0.760 AC: 3325 AN: 4374

European-Finnish (FIN) AF: 0.604 AC: 4897 AN: 8104

Middle Eastern (MID) AF: 0.633 AC: 171 AN: 270

European-Non Finnish (NFE) AF: 0.650 AC: 42571 AN: 65482

Other (OTH) AF: 0.701 AC: 1369 AN: 1954

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

Submissions by phenotype

Niemann-Pick disease, type C1 Benign:8

May 28, 2019

Mendelics

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

- -

Sep 16, 2020

Natera, Inc.

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

- -

Aug 11, 2021

Fulgent Genetics, Fulgent Genetics

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

- -

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. -

not specified Benign:6

Nov 21, 2017

Eurofins Ntd Llc (ga)

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 -

-

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

- -

-

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

Significance: Benign

Review Status: no assertion criteria provided

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

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) -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

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	T
BayesDel_noAF	Benign	-0.31
CADD	Benign	16
DANN	Benign	0.77
DEOGEN2	Benign	0.24	T
Eigen	Benign	-0.69
Eigen_PC	Benign	-0.36
FATHMM_MKL	Benign	0.22	N
LIST_S2	Benign	0.29	T
MetaRNN	Benign	0.0000010	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	-2.1	N
PhyloP100		2.9
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	1.6	N
REVEL	Benign	0.26
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.10
MutPred		0.24		Gain of MoRF binding (P = 0.1764);
MPC		0.28
ClinPred		0.0077	T
GERP RS		5.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.15
gMVP		0.19
Mutation Taster		=84/16	polymorphism

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

Other links and lift over

dbSNP: rs1788799; hg19: chr18-21124945; COSMIC: COSV99342159; COSMIC: COSV99342159;