rs1555345993

Positions:

• chr14-74486379-C-A

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1 PM2 PP3_Strong

The NM_006432.5(NPC2):​c.140G>T​(p.Cys47Phe) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: NPC2 NM_006432.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 7.57

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 Likely_pathogenic. Variant got 8 ACMG points.

• PM1: In a chain NPC intracellular cholesterol transporter 2 (size 131) in uniprot entity NPC2_HUMAN there are 9 pathogenic changes around while only 3 benign (75%) in NM_006432.5
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.994

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NPC2	NM_006432.5	c.140G>T	p.Cys47Phe	missense_variant	2/5	ENST00000555619.6	NP_006423.1
NPC2	NM_001363688.1	c.140G>T	p.Cys47Phe	missense_variant	2/4		NP_001350617.1
NPC2	NM_001375440.1	c.140G>T	p.Cys47Phe	missense_variant	2/4		NP_001362369.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NPC2	ENST00000555619.6	c.140G>T	p.Cys47Phe	missense_variant	2/5	1	NM_006432.5	ENSP00000451112	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1453876 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 722116

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Niemann-Pick disease, type C2 Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Apr 21, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Aug 16, 2022	In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Experimental studies have shown that this missense change affects NPC2 function (PMID: 15937921, 17470133). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 549984). This missense change has been observed in individual(s) with Niemann-Pick Type C disease (PMID: 12955717). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces cysteine, which is neutral and slightly polar, with phenylalanine, which is neutral and non-polar, at codon 47 of the NPC2 protein (p.Cys47Phe). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.49	D
BayesDel_noAF	Pathogenic	0.47
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.82	D;.;D;.;.;.;D
Eigen	Pathogenic	0.90
Eigen_PC	Pathogenic	0.77
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D;D;D;D;D;D;D
M_CAP	Pathogenic	0.36	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	3.8	.;H;H;.;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Uncertain	0.62	T
PROVEAN	Pathogenic	-11	D;D;D;D;D;D;D
REVEL	Pathogenic	0.88
Sift	Uncertain	0.0080	D;D;D;D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D;.;D;.
Polyphen		1.0	.;.;D;.;.;.;.
Vest4		0.95
MutPred		0.96		Loss of catalytic residue at P46 (P = 0.0066);Loss of catalytic residue at P46 (P = 0.0066);Loss of catalytic residue at P46 (P = 0.0066);Loss of catalytic residue at P46 (P = 0.0066);Loss of catalytic residue at P46 (P = 0.0066);Loss of catalytic residue at P46 (P = 0.0066);Loss of catalytic residue at P46 (P = 0.0066);
MVP		1.0
MPC		1.7
ClinPred		1.0	D
GERP RS		5.5
Varity_R		0.99
gMVP		0.99

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs1555345993; hg19: chr14-74953082;