rs104894458

chr14-74484420-G-Achr14-74484420-G-T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Moderate

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 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
• Clinical Significance: Pathogenic criteria provided, single submitter P:3
• Conservation: PhyloP100: 9.75

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]

ACMG classification

Verdict is Pathogenic. Variant got 12 ACMG points.

• PM1: In a chain NPC intracellular cholesterol transporter 2 (size 131) in uniprot entity NPC2_HUMAN there are 18 pathogenic changes around while only 4 benign (82%) in NM_006432.5
• 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 [Likely_pathogenic]. Clinvar id is 2585512.Status of the report is criteria_provided_single_submitter, 1 stars.
• 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]. Clinvar id is 8486.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr14-74484420-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NPC2	NM_006432.5	c.358C>T	p.Pro120Ser	missense_variant	3/5	ENST00000555619.6
NPC2	NM_001363688.1	c.358C>T	p.Pro120Ser	missense_variant	3/4
NPC2	NM_001375440.1	c.358C>T	p.Pro120Ser	missense_variant	3/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NPC2	ENST00000555619.6	c.358C>T	p.Pro120Ser	missense_variant	3/5	1	NM_006432.5	P4

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD3 exomes AF: 0.00000795 AC: 2 AN: 251484 Hom.: 0 AF XY: 0.0000147 AC XY: 2 AN XY: 135918

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 SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000879

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461850 Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 2 AN XY: 727228

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000331

GnomAD4 genome Cov.: 30

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, single submitter

Submissions by phenotype

Niemann-Pick disease, type C2 Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Apr 01, 2007	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Apr 12, 2023	For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects NPC2 function (PMID: 18772377). 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. ClinVar contains an entry for this variant (Variation ID: 8486). 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. This variant is present in population databases (rs104894458, gnomAD 0.003%). 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). -

Niemann-Pick disease, type C1 Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Clinical Genetics Laboratory, University Hospital Schleswig-Holstein

Feb 09, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.95
BayesDel_addAF	Pathogenic	0.49	D
BayesDel_noAF	Pathogenic	0.56
Cadd	Pathogenic	28
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	D
LIST_S2	Uncertain	0.96	D;D;D;D;D;D;D
M_CAP	Pathogenic	0.47	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationTaster	Benign	1.0	A;A;A;A;A
PrimateAI	Uncertain	0.57	T
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	D
GERP RS		5.3
Varity_R		0.95
gMVP		0.92

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: rs104894458; hg19: chr14-74951123;