rs104894458

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PM2PM5PP3_StrongPP5_Very_Strong

The NM_006432.5(NPC2):c.358C>T(p.Pro120Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,850 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P120T) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 30)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

NPC2
NM_006432.5 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5

Conservation

PhyloP100: 9.75

Publications

22 publications found

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 Gene-Disease associations (from GenCC):

Niemann-Pick disease, type C2
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Myriad Women’s Health, G2P, Genomics England PanelApp, Laboratory for Molecular Medicine, ClinGen, Labcorp Genetics (formerly Invitae), Ambry Genetics
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

NPC2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 16 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr14-74484420-G-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 2585512.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.993

PP5

Variant 14-74484420-G-A is Pathogenic according to our data. Variant chr14-74484420-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 8486.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
NPC2	NM_006432.5 link	c.358C>T	p.Pro120Ser	missense_variant	Exon 3 of 5	ENST00000555619.6	NP_006423.1
NPC2	NM_001363688.1 link	c.358C>T	p.Pro120Ser	missense_variant	Exon 3 of 4		NP_001350617.1
NPC2	NM_001375440.1 link	c.358C>T	p.Pro120Ser	missense_variant	Exon 3 of 4		NP_001362369.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NPC2	ENST00000555619.6 link	c.358C>T	p.Pro120Ser	missense_variant	Exon 3 of 5	1	NM_006432.5	ENSP00000451112.2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000795

AC:

AN:

251484

AF XY:

0.0000147

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000879

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000205

AC:

AN:

1461850

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

727228

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26134

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86254

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53416

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111984

Other (OTH)

AF:

0.0000331

AC:

AN:

60390

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Niemann-Pick disease, type C2

Pathogenic:3

Apr 01, 2007

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Jun 12, 2025

Clinical Genetics Laboratory, Skane University Hospital Lund

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

ACMG criteria used: PS3_Supporting, PM2, PM3, PP3. -

Oct 31, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 120 of the NPC2 protein (p.Pro120Ser). This variant is present in population databases (rs104894458, gnomAD 0.003%). This missense change has been observed in individual(s) with Niemann-Pick disease type C (PMID: 16126423, 23791309). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 8486). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects NPC2 function (PMID: 18772377). For these reasons, this variant has been classified as Pathogenic. -

Niemann-Pick disease, type C

Pathogenic:1

Mar 31, 2025

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

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: NPC2 c.358C>T (p.Pro120Ser) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 251484 control chromosomes (gnomAD). c.358C>T has been reported in the literature in homozygous individuals affected with Niemann-Pick Disease Type C (examples: Alavi_2013, Millat_2005). These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 23791309, 16126423). ClinVar contains an entry for this variant (Variation ID: 8486). Based on the evidence outlined above, the variant was classified as pathogenic. -

Niemann-Pick disease, type C1

Pathogenic:1

Feb 09, 2021

Clinical Genetics Laboratory, University Hospital Schleswig-Holstein

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.95

BayesDel_addAF

Pathogenic

0.49

BayesDel_noAF

Pathogenic

0.56

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.79

D;.;D;.;.;.;D

Eigen

Pathogenic

0.96

Eigen_PC

Pathogenic

0.86

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.96

D;D;D;D;D;D;D

M_CAP

Pathogenic

0.47

MetaRNN

Pathogenic

0.99

D;D;D;D;D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

3.8

.;H;H;.;.;.;.

PhyloP100

9.8

PrimateAI

Uncertain

0.57

PROVEAN

Pathogenic

-8.0

D;D;D;D;D;D;D

REVEL

Pathogenic

0.92

Sift

Pathogenic

0.0

D;D;D;D;D;D;D

Sift4G

Pathogenic

0.0

D;D;D;D;.;D;.

Polyphen

1.0

.;.;D;.;.;.;.

Vest4

0.94

MutPred

0.96

Loss of methylation at K123 (P = 0.0611);Loss of methylation at K123 (P = 0.0611);Loss of methylation at K123 (P = 0.0611);Loss of methylation at K123 (P = 0.0611);Loss of methylation at K123 (P = 0.0611);Loss of methylation at K123 (P = 0.0611);Loss of methylation at K123 (P = 0.0611);

MVP

1.0

MPC

1.3

ClinPred

1.0

GERP RS

5.3

Varity_R

0.95

gMVP

0.92

Mutation Taster

=0/100

disease causing (ClinVar)

(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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over