rs80358260

Positions:

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_StrongPM2PP5_Very_Strong

The NM_006432.5(NPC2):c.58G>T(p.Glu20*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00012 in 1,612,162 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).

Frequency

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

Exomes 𝑓: 0.00013 ( 0 hom. )

Consequence

NPC2
NM_006432.5 stop_gained

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:10O:1

Conservation

PhyloP100: 1.08

Variant links:

Genes affected

NPC2 (HGNC:14537): (NPC intracellular cholesterol transporter 2) This gene encodes a protein containing a lipid recognition domain. The encoded protein may function in regulating the transport of cholesterol through the late endosomal/lysosomal system. Mutations in this gene have been associated with Niemann-Pick disease, type C2 and frontal lobe atrophy. [provided by RefSeq, Jul 2008]

NPC2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 14 ACMG points.

PVS1

Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 14 pathogenic variants in the truncated region.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 14-74493217-C-A is Pathogenic according to our data. Variant chr14-74493217-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 8477.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-74493217-C-A is described in Lovd as [Pathogenic]. Variant chr14-74493217-C-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
NPC2	NM_006432.5 linkuse as main transcript	c.58G>T	p.Glu20*	stop_gained	1/5	ENST00000555619.6	NP_006423.1
NPC2	NM_001363688.1 linkuse as main transcript	c.58G>T	p.Glu20*	stop_gained	1/4		NP_001350617.1
NPC2	NM_001375440.1 linkuse as main transcript	c.58G>T	p.Glu20*	stop_gained	1/4		NP_001362369.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NPC2	ENST00000555619.6 linkuse as main transcript	c.58G>T	p.Glu20*	stop_gained	1/5	1	NM_006432.5	ENSP00000451112.2		P61916-1

Frequencies

GnomAD3 genomes

AF:

0.0000723

AC:

AN:

152188

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000942

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000132

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000775

AC:

AN:

245310

Hom.:

AF XY:

0.0000901

AC XY:

AN XY:

133228

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000292

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000163

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000125

AC:

183

AN:

1459974

Hom.:

Cov.:

AF XY:

0.000127

AC XY:

AN XY:

726110

show subpopulations

Gnomad4 AFR exome

AF:

0.0000598

Gnomad4 AMR exome

AF:

0.0000673

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000150

Gnomad4 OTH exome

AF:

0.000182

GnomAD4 genome

AF:

0.0000723

AC:

AN:

152188

Hom.:

Cov.:

AF XY:

0.0000538

AC XY:

AN XY:

74350

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.0000942

Gnomad4 NFE

AF:

0.000132

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000141

Hom.:

Bravo

AF:

0.0000718

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0000660

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.000298

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:10Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Niemann-Pick disease, type C2

Pathogenic:8Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	Jan 28, 2022	ACMG classification criteria: PVS1 very strong, PS3 supporting, PS4 strong, PM2 moderate, PM3 very strong -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Jan 31, 2020	This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 11, 2024	This sequence change creates a premature translational stop signal (p.Glu20*) in the NPC2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in NPC2 are known to be pathogenic (PMID: 25145893). This variant is present in population databases (rs80358260, gnomAD 0.02%). This premature translational stop signal has been observed in individuals with Niemann-Pick disease type C (PMID: 11125141, 26666848). ClinVar contains an entry for this variant (Variation ID: 8477). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 31, 2018	- -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Apr 01, 2007	- -
not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jun 30, 2022	- -
Pathogenic, no assertion criteria provided	clinical testing	Counsyl	Mar 31, 2017	- -

Niemann-Pick disease, type C

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Jun 26, 2017

- -

Inborn genetic diseases

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

May 23, 2022

The c.58G>T (p.E20*) alteration, located in exon 1 (coding exon 1) of the NPC2 gene, consists of a G to T substitution at nucleotide position 58. This changes the amino acid from a glutamic acid (E) to a stop codon at amino acid position 20. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. This alteration has been detected in the homozygous state, and in conjunction with another NPC2 disease-causing alteration, in multiple individuals with Niemann-Pick disease, type C2 (Millat, 2001; Park, 2003; Imrie, 2015; Sudrié-Arnaud, 2021). Based on the available evidence, this alteration is classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.44

BayesDel_noAF

Pathogenic

0.65

CADD

Pathogenic

DANN

Uncertain

1.0

Eigen

Uncertain

0.54

Eigen_PC

Uncertain

0.33

FATHMM_MKL

Uncertain

0.79

Vest4

0.90

GERP RS

3.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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