rs1805081

Positions:

chr18-23560468-T-C

Variant summary

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

The ENST00000269228.10(NPC1):c.644A>G(p.His215Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.379 in 1,613,400 control chromosomes in the GnomAD database, including 123,029 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. H215H) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.29 ( 8271 hom., cov: 32)

Exomes 𝑓: 0.39 ( 114758 hom. )

Consequence

NPC1
ENST00000269228.10 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:15

Conservation

PhyloP100: 0.593

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 topological_domain Lumenal (size 238) in uniprot entity NPC1_HUMAN there are 40 pathogenic changes around while only 17 benign (70%) in ENST00000269228.10

BP4

Computational evidence support a benign effect (MetaRNN=0.0017139614).

BP6

Variant 18-23560468-T-C is Benign according to our data. Variant chr18-23560468-T-C is described in ClinVar as [Benign]. Clinvar id is 92714.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr18-23560468-T-C is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.407 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NPC1	NM_000271.5 linkuse as main transcript	c.644A>G	p.His215Arg	missense_variant	6/25	ENST00000269228.10	NP_000262.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NPC1	ENST00000269228.10 linkuse as main transcript	c.644A>G	p.His215Arg	missense_variant	6/25	1	NM_000271.5	ENSP00000269228	P1	O15118-1
NPC1	ENST00000540608.5 linkuse as main transcript	n.558A>G		non_coding_transcript_exon_variant	4/16	2

Frequencies

GnomAD3 genomes

AF:

0.294

AC:

44703

AN:

152014

Hom.:

8271

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0792

Gnomad AMI

AF:

0.322

Gnomad AMR

AF:

0.269

Gnomad ASJ

AF:

0.257

Gnomad EAS

AF:

0.250

Gnomad SAS

AF:

0.257

Gnomad FIN

AF:

0.478

Gnomad MID

AF:

0.197

Gnomad NFE

AF:

0.411

Gnomad OTH

AF:

0.267

GnomAD3 exomes

AF:

0.331

AC:

82692

AN:

250070

Hom.:

15205

AF XY:

0.336

AC XY:

45507

AN XY:

135354

show subpopulations

Gnomad AFR exome

AF:

0.0702

Gnomad AMR exome

AF:

0.247

Gnomad ASJ exome

AF:

0.260

Gnomad EAS exome

AF:

0.246

Gnomad SAS exome

AF:

0.278

Gnomad FIN exome

AF:

0.457

Gnomad NFE exome

AF:

0.404

Gnomad OTH exome

AF:

0.330

GnomAD4 exome

AF:

0.388

AC:

566798

AN:

1461268

Hom.:

114758

Cov.:

AF XY:

0.385

AC XY:

279556

AN XY:

726982

show subpopulations

Gnomad4 AFR exome

AF:

0.0597

Gnomad4 AMR exome

AF:

0.253

Gnomad4 ASJ exome

AF:

0.258

Gnomad4 EAS exome

AF:

0.267

Gnomad4 SAS exome

AF:

0.280

Gnomad4 FIN exome

AF:

0.454

Gnomad4 NFE exome

AF:

0.419

Gnomad4 OTH exome

AF:

0.349

GnomAD4 genome

AF:

0.294

AC:

44713

AN:

152132

Hom.:

8271

Cov.:

AF XY:

0.293

AC XY:

21757

AN XY:

74360

show subpopulations

Gnomad4 AFR

AF:

0.0790

Gnomad4 AMR

AF:

0.269

Gnomad4 ASJ

AF:

0.257

Gnomad4 EAS

AF:

0.250

Gnomad4 SAS

AF:

0.258

Gnomad4 FIN

AF:

0.478

Gnomad4 NFE

AF:

0.411

Gnomad4 OTH

AF:

0.271

Alfa

AF:

0.372

Hom.:

27372

Bravo

AF:

0.269

TwinsUK

AF:

0.420

AC:

1557

ALSPAC

AF:

0.427

AC:

1645

ESP6500AA

AF:

0.0878

AC:

387

ESP6500EA

AF:

0.403

AC:

3462

ExAC

AF:

0.327

AC:

39711

Asia WGS

AF:

0.231

AC:

804

AN:

3478

EpiCase

AF:

0.387

EpiControl

AF:

0.371

ClinVar

Significance: Benign

Submissions summary: Benign:15

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Niemann-Pick disease, type C1

Benign:7

Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	Sep 21, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 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, 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	Oct 05, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jun 10, 2021	- -

not specified

Benign:6

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	Eurofins Ntd Llc (ga)	Jul 24, 2015	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
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 -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

not provided

Benign:2

Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Oct 21, 2015	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.052

BayesDel_addAF

Benign

-0.58

BayesDel_noAF

Benign

-0.46

CADD

Benign

5.3

DANN

Benign

0.45

DEOGEN2

Uncertain

0.48

Eigen

Benign

-0.96

Eigen_PC

Benign

-0.93

FATHMM_MKL

Benign

0.28

LIST_S2

Benign

0.59

MetaRNN

Benign

0.0017

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.2

MutationTaster

Benign

1.0

PrimateAI

Benign

0.35

PROVEAN

Benign

-1.4

REVEL

Benign

0.15

Sift

Benign

0.53

Sift4G

Benign

0.58

Polyphen

0.0

Vest4

0.026

MPC

0.31

ClinPred

0.0039

GERP RS

-1.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.11

gMVP

0.29

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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