chr18-23560403-G-A

Variant names:

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 1P and 13B. PP2BP4_StrongBP6BS1BS2

The NM_000271.5(NPC1):c.709C>T(p.Pro237Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0134 in 1,614,168 control chromosomes in the GnomAD database, including 195 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P237L) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.010 ( 17 hom., cov: 32)

Exomes 𝑓: 0.014 ( 178 hom. )

Consequence

NPC1
NM_000271.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:14O:1

Conservation

PhyloP100: 8.19

Publications

48 publications found

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 Gene-Disease associations (from GenCC):

Niemann-Pick disease, type C1
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: ClinGen, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Myriad Women’s Health, Laboratory for Molecular Medicine, G2P
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

NPC1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

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 C, severe early infantile neurologic onset, Niemann-Pick disease type C, late infantile neurologic onset, Niemann-Pick disease type C, juvenile neurologic onset, Niemann-Pick disease type C, severe perinatal form, Niemann-Pick disease type C, adult neurologic onset, Niemann-Pick disease, type C1.

BP4

Computational evidence support a benign effect (MetaRNN=0.013225466).

BP6

Variant 18-23560403-G-A is Benign according to our data. Variant chr18-23560403-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 21142.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.01 (1528/152344) while in subpopulation NFE AF = 0.0162 (1100/68034). AF 95% confidence interval is 0.0154. There are 17 homozygotes in GnomAd4. There are 720 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 17 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000271.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NPC1	NM_000271.5	MANE Select	c.709C>T	p.Pro237Ser	missense	Exon 6 of 25	NP_000262.2	O15118-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
NPC1	ENST00000269228.10	TSL:1 MANE Select	c.709C>T	p.Pro237Ser	missense	Exon 6 of 25	ENSP00000269228.4	O15118-1
NPC1	ENST00000897526.1		c.709C>T	p.Pro237Ser	missense	Exon 6 of 25	ENSP00000567585.1
NPC1	ENST00000926494.1		c.709C>T	p.Pro237Ser	missense	Exon 6 of 25	ENSP00000596553.1

Frequencies

GnomAD3 genomes

AF:

0.0101

AC:

1530

AN:

152226

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00277

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00543

Gnomad ASJ

AF:

0.00461

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00103

Gnomad FIN

AF:

0.0186

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0162

Gnomad OTH

AF:

0.00621

GnomAD2 exomes

AF:

0.00988

AC:

2478

AN:

250694

AF XY:

0.00961

show subpopulations

Gnomad AFR exome

AF:

0.00296

Gnomad AMR exome

AF:

0.00370

Gnomad ASJ exome

AF:

0.00289

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0177

Gnomad NFE exome

AF:

0.0159

Gnomad OTH exome

AF:

0.0105

GnomAD4 exome

AF:

0.0138

AC:

20169

AN:

1461824

Hom.:

178

Cov.:

AF XY:

0.0133

AC XY:

9695

AN XY:

727222

show subpopulations

African (AFR)

AF:

0.00212

AC:

AN:

33480

American (AMR)

AF:

0.00423

AC:

189

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00314

AC:

AN:

26136

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39698

South Asian (SAS)

AF:

0.00103

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.0198

AC:

1055

AN:

53410

Middle Eastern (MID)

AF:

0.00174

AC:

AN:

5760

European-Non Finnish (NFE)

AF:

0.0161

AC:

17949

AN:

1111964

Other (OTH)

AF:

0.0120

AC:

723

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.459

Heterozygous variant carriers

1041

2081

3122

4162

5203

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

674

1348

2022

2696

3370

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0100

AC:

1528

AN:

152344

Hom.:

Cov.:

AF XY:

0.00966

AC XY:

720

AN XY:

74510

show subpopulations

African (AFR)

AF:

0.00277

AC:

115

AN:

41574

American (AMR)

AF:

0.00542

AC:

AN:

15308

Ashkenazi Jewish (ASJ)

AF:

0.00461

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5188

South Asian (SAS)

AF:

0.000828

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.0186

AC:

197

AN:

10616

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0162

AC:

1100

AN:

68034

Other (OTH)

AF:

0.00614

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

164

247

329

411

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0132

Hom.:

Bravo

AF:

0.00840

TwinsUK

AF:

0.0202

AC:

ALSPAC

AF:

0.0150

AC:

ESP6500AA

AF:

0.00295

AC:

ESP6500EA

AF:

0.0159

AC:

137

ExAC

AF:

0.0104

AC:

1263

Asia WGS

AF:

0.00144

AC:

AN:

3478

EpiCase

AF:

0.0144

EpiControl

AF:

0.0133

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Niemann-Pick disease, type C1 (7)

not specified (5)

not provided (3)

Nasopharyngeal carcinoma (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.096

BayesDel_noAF

Uncertain

0.11

CADD

Benign

(source)

DANN

Benign

0.85

DEOGEN2

Uncertain

0.43

Eigen

Benign

-0.12

Eigen_PC

Benign

0.012

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.87

MetaRNN

Benign

0.013

MetaSVM

Uncertain

-0.22

MutationAssessor

Uncertain

2.2

PhyloP100

8.2

PrimateAI

Benign

0.47

PROVEAN

Benign

-2.2

REVEL

Uncertain

0.40

Sift

Benign

0.41

Sift4G

Benign

0.52

Polyphen

0.0030

Vest4

0.42

MPC

0.27

ClinPred

0.076

GERP RS

5.9

PromoterAI

0.018

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.18

gMVP

0.73

Mutation Taster

=70/30

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over