rs80358262

Positions:

• chr14-74486386-G-A

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_006432.5(NPC2):​c.133C>T​(p.Gln45*) variant causes a stop gained change involving the alteration of a non-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 Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: NPC2 NM_006432.5 stop_gained
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4 O:1
• Conservation: PhyloP100: 3.06

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 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 14-74486386-G-A is Pathogenic according to our data. Variant chr14-74486386-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 21455.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NPC2	NM_006432.5	c.133C>T	p.Gln45*	stop_gained	2/5	ENST00000555619.6	NP_006423.1
NPC2	NM_001363688.1	c.133C>T	p.Gln45*	stop_gained	2/4		NP_001350617.1
NPC2	NM_001375440.1	c.133C>T	p.Gln45*	stop_gained	2/4		NP_001362369.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NPC2	ENST00000555619.6	c.133C>T	p.Gln45*	stop_gained	2/5	1	NM_006432.5	ENSP00000451112.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1453886 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 722134

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: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Niemann-Pick disease, type C2 Pathogenic:3 Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Apr 24, 2023	For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 21455). This premature translational stop signal has been observed in individual(s) with Niemann-Pick type C (PMID: 15937921). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Gln45*) 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). -
not provided, no classification provided	literature only	GeneReviews	-	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Aug 17, 2018	The NPC2 c.133C>T (p.Gln45Ter) variant is a stop-gained variant predicted to result in premature termination of the protein. The p.Gln45Ter variant has been reported in at least two studies in which it is found in a homozygous state in a total of two patients with Niemann-Pick Disease type C (NPC) (Chikh et al. 2005; Boenzi et al. 2014). Control data is unavailable for the p.Gln45Ter variant, which is not found in the 1000 Genomes Project, the Exome Sequencing Project, Exome Aggregation Consortium or the Genome Aggregation Database, in a region of good sequence coverage, and hence is presumed to be rare. Functional studies using patient-derived fibroblasts isolated from two patients demonstrated that the p.Gln45Ter variant affected intracellular cholesterol processing to the degree previously associated with classic NPC (Chikh et al. 2005; Boenzi et al. 2014). Additionally, LC-MS/MS testing of the p.Gln45Ter patient-derived plasma oxysterols revealed pathogenic levels of C-triol and 7-KC compared to normal controls (Boenzi et al. 2014). Based on the collective evidence, the p.Gln45Ter variant is classified as likely pathogenic for Niemann-Pick Disease type C. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Feb 03, 2020	- -

Niemann-Pick disease, type C Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

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

Sep 23, 2019

Variant summary: NPC2 c.133C>T (p.Gln45X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. A truncation downstream of this position has been classified as pathogenic by our laboratory. The variant was absent in 236558 control chromosomes (gnomAD). The variant, c.133C>T, has been reported in the literature in two homozygous individuals affected with Niemann-Pick Disease Type C (Vanier_2004, Chikh_2005, Boenzi_2014). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.48
CADD	Pathogenic	35
DANN	Uncertain	0.99
Eigen	Uncertain	0.32
Eigen_PC	Benign	0.053
FATHMM_MKL	Uncertain	0.92	D
Vest4		0.96
GERP RS		2.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs80358262; hg19: chr14-74953089;