18-23541154-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 2P and 16B. PM2BP4_StrongBP6_Very_StrongBS1

The NM_000271.5(NPC1):c.2428G>A(p.Val810Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000135 in 1,614,194 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V810F) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000072 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00014 ( 0 hom. )

Consequence

NPC1
NM_000271.5 missense

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -1.83

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 -14 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.008728087).

BP6

Variant 18-23541154-C-T is Benign according to our data. Variant chr18-23541154-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 833897.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr18-23541154-C-T is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population sas. gnomad4_exome allele frequency = 0.000142 (207/1461880) while in subpopulation SAS AF= 0.0019 (164/86258). AF 95% confidence interval is 0.00166. There are 0 homozygotes in gnomad4_exome. There are 147 alleles in male gnomad4_exome subpopulation. Median coverage is 32. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NPC1	NM_000271.5 linkuse as main transcript	c.2428G>A	p.Val810Ile	missense_variant	16/25	ENST00000269228.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NPC1	ENST00000269228.10 linkuse as main transcript	c.2428G>A	p.Val810Ile	missense_variant	16/25	1	NM_000271.5	P1	O15118-1
NPC1	ENST00000591051.1 linkuse as main transcript	c.1507G>A	p.Val503Ile	missense_variant	9/18	2
NPC1	ENST00000540608.5 linkuse as main transcript	n.2342G>A		non_coding_transcript_exon_variant	14/16	2
NPC1	ENST00000586718.1 linkuse as main transcript	n.219G>A		non_coding_transcript_exon_variant	1/3	3

Frequencies

GnomAD3 genomes

AF:

0.0000723

AC:

AN:

152196

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000482

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00124

Gnomad FIN

AF:

0.0000942

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000227

AC:

AN:

251482

Hom.:

AF XY:

0.000316

AC XY:

AN XY:

135912

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00176

Gnomad FIN exome

AF:

0.0000462

Gnomad NFE exome

AF:

0.00000879

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000142

AC:

207

AN:

1461880

Hom.:

Cov.:

AF XY:

0.000202

AC XY:

147

AN XY:

727242

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.0000447

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000227

Gnomad4 SAS exome

AF:

0.00190

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000225

Gnomad4 OTH exome

AF:

0.0000662

GnomAD4 genome

AF:

0.0000722

AC:

AN:

152314

Hom.:

Cov.:

AF XY:

0.0000806

AC XY:

AN XY:

74480

show subpopulations

Gnomad4 AFR

AF:

0.0000481

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00124

Gnomad4 FIN

AF:

0.0000942

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000416

ExAC

AF:

0.000264

AC:

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

NPC1-related disorder

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 20, 2022

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). -

Niemann-Pick disease, type C1

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 25, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.064

BayesDel_addAF

Benign

-0.49

BayesDel_noAF

Benign

-0.48

Cadd

Benign

0.12

Dann

Benign

0.78

DEOGEN2

Benign

0.28

Eigen

Benign

-1.4

Eigen_PC

Benign

-1.5

FATHMM_MKL

Benign

0.12

LIST_S2

Benign

0.64

M_CAP

Benign

0.062

MetaRNN

Benign

0.0087

MetaSVM

Benign

-0.56

MutationAssessor

Benign

0.60

MutationTaster

Benign

1.0

N;N

PrimateAI

Benign

0.25

PROVEAN

Benign

-0.48

REVEL

Benign

0.13

Sift

Benign

0.24

Sift4G

Benign

0.23

Polyphen

0.0

Vest4

0.13

MVP

0.43

MPC

0.21

ClinPred

0.024

GERP RS

-9.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.023

gMVP

0.15

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