chr18-23560447-T-C

Variant summary

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

The NM_000271.5(NPC1):ā€‹c.665A>Gā€‹(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: š‘“ 0.0033 ( 0 hom., cov: 32)
Exomes š‘“: 0.0056 ( 37 hom. )

Consequence

NPC1
NM_000271.5 missense

Scores

1
5
13

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]

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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
NPC1NM_000271.5 linkc.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
NPC1ENST00000269228.10 linkc.665A>G p.Asn222Ser missense_variant Exon 6 of 25 1 NM_000271.5 ENSP00000269228.4 O15118-1
NPC1ENST00000540608.5 linkn.579A>G non_coding_transcript_exon_variant Exon 4 of 16 2

Frequencies

GnomAD3 genomes
AF:
0.00332
AC:
506
AN:
152204
Hom.:
0
Cov.:
32
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.:
0
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.:
37
Cov.:
32
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.:
0
Cov.:
32
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.:
5
Bravo
AF:
0.00372
TwinsUK
AF:
0.00728
AC:
27
ALSPAC
AF:
0.00545
AC:
21
ESP6500AA
AF:
0.00159
AC:
7
ESP6500EA
AF:
0.00605
AC:
52
ExAC
AF:
0.00352
AC:
428
Asia WGS
AF:
0.00173
AC:
6
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
May 18, 2021
Genome-Nilou Lab
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Feb 03, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Dec 30, 2019
Natera, Inc.
Significance: Likely benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

-
GenomeConnect, ClinGen
Significance: not provided
Review Status: no classification provided
Collection Method: phenotyping only

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. -

Apr 27, 2017
Illumina Laboratory Services, Illumina
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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
Jun 04, 2015
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Jan 06, 2020
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Dec 01, 2024
CeGaT Center for Human Genetics Tuebingen
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

NPC1: BS2 -

Feb 24, 2023
Mayo Clinic Laboratories, Mayo Clinic
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

BS1 -

not specified Benign:2
Sep 22, 2015
Eurofins Ntd Llc (ga)
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Jul 21, 2023
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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
Jun 25, 2021
Ambry Genetics
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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
May 24, 2019
PreventionGenetics, part of Exact Sciences
Significance: Likely benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

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
T
BayesDel_noAF
Benign
-0.20
CADD
Benign
20
DANN
Benign
0.40
DEOGEN2
Benign
0.40
T
Eigen
Benign
-0.088
Eigen_PC
Benign
0.11
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.92
D
M_CAP
Benign
0.034
D
MetaRNN
Benign
0.017
T
MetaSVM
Uncertain
-0.13
T
MutationAssessor
Uncertain
2.3
M
PrimateAI
Uncertain
0.49
T
PROVEAN
Benign
-1.2
N
REVEL
Uncertain
0.35
Sift
Benign
0.72
T
Sift4G
Benign
0.80
T
Polyphen
0.0030
B
Vest4
0.70
MVP
0.83
MPC
0.23
ClinPred
0.037
T
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.

Other links and lift over

dbSNP: rs55680026; hg19: chr18-21140411; COSMIC: COSV99340714; COSMIC: COSV99340714; API