chr18-23560447-T-C

Variant names:

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_StrongBS1BS2

The NM_000271.5(NPC1):c.665A>G(p.Asn222Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00537 in 1,614,122 control chromosomes in the GnomAD database, including 37 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 Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0033 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0056 ( 37 hom. )

Consequence

NPC1
NM_000271.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4B:8O:1

Conservation

PhyloP100: 6.12

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 -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.016513348).

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00332 (506/152322) while in subpopulation NFE AF= 0.00542 (369/68020). AF 95% confidence interval is 0.00497. There are 0 homozygotes in gnomad4. There are 234 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAdExome4 at 37 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NPC1	NM_000271.5 link	c.665A>G	p.Asn222Ser	missense_variant	Exon 6 of 25	ENST00000269228.10	NP_000262.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NPC1	ENST00000269228.10 link	c.665A>G	p.Asn222Ser	missense_variant	Exon 6 of 25	1	NM_000271.5	ENSP00000269228.4		O15118-1
NPC1	ENST00000540608.5 link	n.579A>G		non_coding_transcript_exon_variant	Exon 4 of 16	2

Frequencies

GnomAD3 genomes

AF:

0.00332

AC:

506

AN:

152204

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00104

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00458

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00228

Gnomad FIN

AF:

0.000753

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00542

Gnomad OTH

AF:

0.00239

GnomAD3 exomes

AF:

0.00336

AC:

842

AN:

250650

Hom.:

AF XY:

0.00360

AC XY:

488

AN XY:

135548

show subpopulations

Gnomad AFR exome

AF:

0.000988

Gnomad AMR exome

AF:

0.00336

Gnomad ASJ exome

AF:

0.0000995

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.00262

Gnomad FIN exome

AF:

0.000786

Gnomad NFE exome

AF:

0.00515

Gnomad OTH exome

AF:

0.00474

GnomAD4 exome

AF:

0.00558

AC:

8164

AN:

1461800

Hom.:

Cov.:

AF XY:

0.00556

AC XY:

4043

AN XY:

727198

show subpopulations

Gnomad4 AFR exome

AF:

0.000568

Gnomad4 AMR exome

AF:

0.00326

Gnomad4 ASJ exome

AF:

0.000115

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.00292

Gnomad4 FIN exome

AF:

0.000899

Gnomad4 NFE exome

AF:

0.00660

Gnomad4 OTH exome

AF:

0.00565

GnomAD4 genome

AF:

0.00332

AC:

506

AN:

152322

Hom.:

Cov.:

AF XY:

0.00314

AC XY:

234

AN XY:

74494

show subpopulations

Gnomad4 AFR

AF:

0.00103

Gnomad4 AMR

AF:

0.00458

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00228

Gnomad4 FIN

AF:

0.000753

Gnomad4 NFE

AF:

0.00542

Gnomad4 OTH

AF:

0.00236

Alfa

AF:

0.00469

Hom.:

Bravo

AF:

0.00372

TwinsUK

AF:

0.00728

AC:

ALSPAC

AF:

0.00545

AC:

ESP6500AA

AF:

0.00159

AC:

ESP6500EA

AF:

0.00605

AC:

ExAC

AF:

0.00352

AC:

428

Asia WGS

AF:

0.00173

AC:

AN:

3478

EpiCase

AF:

0.00513

EpiControl

AF:

0.00545

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4Benign:8Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Niemann-Pick disease, type C1

Uncertain:2Benign:2Other:1

Uncertain significance, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	May 18, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 03, 2025	- -
Likely benign, no assertion criteria provided	clinical testing	Natera, Inc.	Dec 30, 2019	- -
not provided, no classification provided	phenotyping only	GenomeConnect, ClinGen	-	GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

not provided

Uncertain:2Benign:2

Uncertain significance, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Jun 04, 2015	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jan 06, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Dec 01, 2024	NPC1: BS2 -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Feb 24, 2023	BS1 -

not specified

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Sep 22, 2015	- -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jul 21, 2023	Variant summary: NPC1 c.665A>G (p.Asn222Ser) results in a conservative amino acid change located in the Niemann-Pick C1, N-terminal domain (IPR032190) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0034 in 250650 control chromosomes (gnomAD), predominantly at a frequency of 0.0051 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 2 fold of the estimated maximal expected allele frequency for a pathogenic variant in NPC1 causing Niemann-Pick Disease Type C (0.0027), suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin.c.665A>G has been reported in the literature in multiple individuals presenting with varying phenotypes from Niemann-Pick Disease Type C, late-onset/adult and late infantile forms, familial epileptogenic encephalopathy with a peculiar form of degenerative glial tauopathy, neonatal cholestasis, epilepsy and psycotic symptoms, splenomegaly, and low and high HDL-C (Cupidi_2018, DeCastro-Oros_2017, Fancello_2009, Imrie_2007, Park_2003, Romanello_2016, Sadananda_2015, Stampfer_2013, Wassif_2016, Dardis_2020, Touma_2020 and Lopez de Fruto_2021). The variant has presented in isolation (no second NPC1 allele identified), as a compound heterozygote with another pathogenic NPC1 variant (I1061T, P1007A) and in co-occurrence with two additional pathogenic NPC1 variants (I1061T/R958Q - phase is not known). The variant was also detected in homozygous state in one young obese patient without other phenotypic information provided (Liu_2017). These reports do not provide unequivocal conclusions about association of the variant with Niemann-Pick Disease Type C. Experimental evidence evaluating an impact on protein function demonstrated that the variant protein was secreted and showed normal behavior and cellular localization, while protein expression and cholesterol transporting ability were similar to wild type (Liu_2017, Infante_2008). The following publications have been ascertained in the context of this evaluation (PMID: 32138288, 28222799, 30153451, 19252935, 17160617, 17989072, 28130309, 32745579, 12955717, 26790753, 26255038, 23433426, 33990640, 25764212). Nine ClinVar submitters have assessed the variant since 2014: four classified the variant as uncertain significance, four as likely benign, and one as benign. Based on the evidence outlined above, the variant was classified as likely benign. -

Inborn genetic diseases

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 25, 2021

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

NPC1-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

May 24, 2019

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.30

BayesDel_noAF

Benign

-0.20

CADD

Benign

DANN

Benign

0.40

DEOGEN2

Benign

0.40

Eigen

Benign

-0.088

Eigen_PC

Benign

0.11

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.92

M_CAP

Benign

0.034

MetaRNN

Benign

0.017

MetaSVM

Uncertain

-0.13

MutationAssessor

Uncertain

2.3

PrimateAI

Uncertain

0.49

PROVEAN

Benign

-1.2

REVEL

Uncertain

0.35

Sift

Benign

0.72

Sift4G

Benign

0.80

Polyphen

0.0030

Vest4

0.70

MVP

0.83

MPC

0.23

ClinPred

0.037

GERP RS

5.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.54

gMVP

0.60

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