chr18-23560447-T-C

Variant names:

• chr18-23560447-T-C
• rs55680026
• NM_000271.5:c.665A>G

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 3P and 12B. PM1 PP2 BP4_Strong BS1 BS2

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. 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
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:8 O:1
• Conservation: PhyloP100: 6.12

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

Our verdict: Benign. The variant received -9 ACMG points.

• PM1: In a mutagenesis_site Decreases affinity for NPC2. Abolishes cholesterol transfer from NPC2 to NPC1. (size 232) in uniprot entity NPC1_HUMAN there are 41 pathogenic changes around while only 17 benign (71%) 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, juvenile neurologic onset, Niemann-Pick disease type C, severe early infantile neurologic onset, Niemann-Pick disease type C, severe perinatal form, Niemann-Pick disease type C, adult neurologic onset, Niemann-Pick disease type C, late infantile neurologic onset.
• 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 the male GnomAd4 subpopulation. Median coverage is 32. This position FAILED quality control check.
• 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	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	c.665A>G	p.Asn222Ser	missense_variant	Exon 6 of 25	1	NM_000271.5	ENSP00000269228.4
NPC1	ENST00000540608.5	n.579A>G		non_coding_transcript_exon_variant	Exon 4 of 16	2
NPC1	ENST00000591051.1	c.-107A>G		upstream_gene_variant		2		ENSP00000467636.1

Frequencies

GnomAD3 genomes AF: 0.00332 AC: 506 AN: 152204 Hom.: 0 Cov.: 32

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

GnomAD2 exomes AF: 0.00336 AC: 842 AN: 250650 AF XY: 0.00360

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 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

Gnomad4 AFR exome AF: 0.000568 AC: 19 AN: 33480

Gnomad4 AMR exome AF: 0.00326 AC: 146 AN: 44722

Gnomad4 ASJ exome AF: 0.000115 AC: 3 AN: 26136

Gnomad4 EAS exome AF: 0.0000504 AC: 2 AN: 39700

Gnomad4 SAS exome AF: 0.00292 AC: 252 AN: 86256

Gnomad4 FIN exome AF: 0.000899 AC: 48 AN: 53402

Gnomad4 NFE exome AF: 0.00660 AC: 7344 AN: 1111964

Gnomad4 Remaining exome AF: 0.00565 AC: 341 AN: 60388

GnomAD4 genome AF: 0.00332 AC: 506 AN: 152322 Hom.: 0 Cov.: 32 AF XY: 0.00314 AC XY: 234 AN XY: 74494

Gnomad4 AFR AF: 0.00103 AC: 0.00103455 AN: 0.00103455

Gnomad4 AMR AF: 0.00458 AC: 0.00457516 AN: 0.00457516

Gnomad4 ASJ AF: 0.00 AC: 0 AN: 0

Gnomad4 EAS AF: 0.00 AC: 0 AN: 0

Gnomad4 SAS AF: 0.00228 AC: 0.00227743 AN: 0.00227743

Gnomad4 FIN AF: 0.000753 AC: 0.000753296 AN: 0.000753296

Gnomad4 NFE AF: 0.00542 AC: 0.00542488 AN: 0.00542488

Gnomad4 OTH AF: 0.00236 AC: 0.00236295 AN: 0.00236295

Alfa AF: 0.00437 Hom.: 8

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:4 Benign:8 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Niemann-Pick disease, type C1 Uncertain:2 Benign:2 Other: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:2 Benign:2

Feb 24, 2023

Mayo Clinic Laboratories, Mayo Clinic

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

BS1 -

Dec 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

NPC1: BS2 -

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

- -

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
Mutation Taster		=60/40	polymorphism

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