chr18-23544981-C-G

Position:

• chr18-23544981-C-G

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1 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. 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 same amino acid change has been previously reported as Benignin 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

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]

ACMG classification

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 0 benign, 4 uncertain 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/exons	MANE	UniProt
NPC1	NM_000271.5	c.1926G>C	p.Met642Ile	missense_variant	12/25	ENST00000269228.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NPC1	ENST00000269228.10	c.1926G>C	p.Met642Ile	missense_variant	12/25	1	NM_000271.5	P1
NPC1	ENST00000591051.1	c.1005G>C	p.Met335Ile	missense_variant	5/18	2
NPC1	ENST00000540608.5	n.1840G>C		non_coding_transcript_exon_variant	10/16	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

GnomAD3 exomes AF: 0.729 AC: 174136 AN: 238838 Hom.: 66404 AF XY: 0.720 AC XY: 93040 AN XY: 129148

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

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.: 22 AF XY: 0.739 AC XY: 50240 AN XY: 67968

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

Submissions by phenotype

Niemann-Pick disease, type C1 Benign:8

Benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Aug 11, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jun 10, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	Apr 22, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 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, 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 specified Benign:6

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	-	- -
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	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 21, 2017	- -
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 -

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	This variant is associated with the following publications: (PMID: 23153210) -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Oct 23, 2015	- -

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
MutationTaster	Benign	1.0	P;P
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

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

Other links and lift over

dbSNP: rs1788799; hg19: chr18-21124945;