18-23540480-T-C

Variant names:

• chr18-23540480-T-C
• rs1805082
• NM_000271.5:c.2572A>G

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.2572A>G​(p.Ile858Val) variant causes a missense change. The variant allele was found at a frequency of 0.487 in 1,607,602 control chromosomes in the GnomAD database, including 193,451 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 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 Likely benign in ClinVar.

• Frequency:
  • Genomes: 𝑓 0.47 (16781 hom., cov: 31)
  • Exomes 𝑓: 0.49 (176670 hom.)
• Consequence: NPC1 NM_000271.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:16 O:1
• Conservation: PhyloP100: 4.93
• Publications: 86 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 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 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=7.40361E-5).
• BP6: Variant 18-23540480-T-C is Benign according to our data. Variant chr18-23540480-T-C is described in CliVar as Benign. Clinvar id is 21135.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr18-23540480-T-C is described in CliVar as Benign. Clinvar id is 21135.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr18-23540480-T-C is described in CliVar as Benign. Clinvar id is 21135.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr18-23540480-T-C is described in CliVar as Benign. Clinvar id is 21135.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr18-23540480-T-C is described in CliVar as Benign. Clinvar id is 21135.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr18-23540480-T-C is described in CliVar as Benign. Clinvar id is 21135.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr18-23540480-T-C is described in CliVar as Benign. Clinvar id is 21135.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr18-23540480-T-C is described in CliVar as Benign. Clinvar id is 21135.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr18-23540480-T-C is described in CliVar as Benign. Clinvar id is 21135.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr18-23540480-T-C is described in CliVar as Benign. Clinvar id is 21135.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr18-23540480-T-C is described in CliVar as Benign. Clinvar id is 21135.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr18-23540480-T-C is described in CliVar as Benign. Clinvar id is 21135.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr18-23540480-T-C is described in CliVar as Benign. Clinvar id is 21135.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr18-23540480-T-C is described in CliVar as Benign. Clinvar id is 21135.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr18-23540480-T-C is described in CliVar as Benign. Clinvar id is 21135.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr18-23540480-T-C is described in CliVar as Benign. Clinvar id is 21135.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr18-23540480-T-C is described in CliVar as Benign. Clinvar id is 21135.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.612 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NPC1	NM_000271.5	c.2572A>G	p.Ile858Val	missense_variant	Exon 17 of 25	ENST00000269228.10	NP_000262.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NPC1	ENST00000269228.10	c.2572A>G	p.Ile858Val	missense_variant	Exon 17 of 25	1	NM_000271.5	ENSP00000269228.4
NPC1	ENST00000591051.1	c.1648A>G	p.Ile550Val	missense_variant	Exon 10 of 18	2		ENSP00000467636.1
NPC1	ENST00000540608.5	n.2486A>G		non_coding_transcript_exon_variant	Exon 15 of 16	2
NPC1	ENST00000586718.1	n.363A>G		non_coding_transcript_exon_variant	Exon 2 of 3	3

Frequencies

GnomAD3 genomes AF: 0.466 AC: 70363 AN: 151124 Hom.: 16762 Cov.: 31

Gnomad AFR AF: 0.380

Gnomad AMI AF: 0.425

Gnomad AMR AF: 0.573

Gnomad ASJ AF: 0.308

Gnomad EAS AF: 0.630

Gnomad SAS AF: 0.492

Gnomad FIN AF: 0.534

Gnomad MID AF: 0.304

Gnomad NFE AF: 0.479

Gnomad OTH AF: 0.444

GnomAD2 exomes AF: 0.499 AC: 125161 AN: 250608 AF XY: 0.493

Gnomad AFR exome AF: 0.378

Gnomad AMR exome AF: 0.654

Gnomad ASJ exome AF: 0.307

Gnomad EAS exome AF: 0.624

Gnomad FIN exome AF: 0.503

Gnomad NFE exome AF: 0.470

Gnomad OTH exome AF: 0.467

GnomAD4 exome AF: 0.489 AC: 711784 AN: 1456382 Hom.: 176670 Cov.: 34 AF XY: 0.487 AC XY: 352658 AN XY: 724846

African (AFR) AF: 0.369 AC: 12301 AN: 33376

American (AMR) AF: 0.645 AC: 28844 AN: 44700

Ashkenazi Jewish (ASJ) AF: 0.303 AC: 7915 AN: 26106

East Asian (EAS) AF: 0.657 AC: 26077 AN: 39672

South Asian (SAS) AF: 0.493 AC: 42500 AN: 86130

European-Finnish (FIN) AF: 0.498 AC: 26433 AN: 53120

Middle Eastern (MID) AF: 0.347 AC: 1997 AN: 5760

European-Non Finnish (NFE) AF: 0.485 AC: 537500 AN: 1107314

Other (OTH) AF: 0.469 AC: 28217 AN: 60204

GnomAD4 genome AF: 0.466 AC: 70442 AN: 151220 Hom.: 16781 Cov.: 31 AF XY: 0.470 AC XY: 34739 AN XY: 73838

African (AFR) AF: 0.380 AC: 15622 AN: 41110

American (AMR) AF: 0.574 AC: 8758 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.308 AC: 1067 AN: 3466

East Asian (EAS) AF: 0.630 AC: 3250 AN: 5160

South Asian (SAS) AF: 0.493 AC: 2358 AN: 4780

European-Finnish (FIN) AF: 0.534 AC: 5496 AN: 10286

Middle Eastern (MID) AF: 0.311 AC: 89 AN: 286

European-Non Finnish (NFE) AF: 0.479 AC: 32480 AN: 67876

Other (OTH) AF: 0.449 AC: 935 AN: 2084

Alfa AF: 0.470 Hom.: 67432

Bravo AF: 0.467

TwinsUK AF: 0.494 AC: 1833

ALSPAC AF: 0.496 AC: 1911

ESP6500AA AF: 0.388 AC: 1711

ESP6500EA AF: 0.471 AC: 4047

ExAC AF: 0.490 AC: 59504

Asia WGS AF: 0.549 AC: 1908 AN: 3478

EpiCase AF: 0.456

EpiControl AF: 0.445

ClinVar

Significance: Benign

Submissions summary: Benign:16 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Niemann-Pick disease, type C1 Benign:7 Other:1

Jun 10, 2021

Genome-Nilou Lab

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

- -

-

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

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

- -

Sep 21, 2015

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

- -

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. -

not specified Benign:6

-

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

- -

Jul 24, 2015

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. -

-

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

Significance: Benign

Review Status: no assertion criteria provided

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 -

not provided Benign:3

Oct 20, 2015

Mayo Clinic Laboratories, Mayo Clinic

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.059
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.12
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.29	T
Eigen	Benign	-0.054
Eigen_PC	Benign	0.17
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.69	T
MetaRNN	Benign	0.000074	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	1.3	L
PhyloP100		4.9
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-0.72	N
REVEL	Uncertain	0.33
Sift	Benign	0.23	T
Sift4G	Benign	0.28	T
Polyphen		0.047	B
Vest4		0.075
MPC		0.22
ClinPred		0.0081	T
GERP RS		6.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.28
gMVP		0.39
Mutation Taster		=91/9	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.10		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: rs1805082; hg19: chr18-21120444; COSMIC: COSV52582772; COSMIC: COSV52582772;