rs80358262

Variant names:

• chr14-74486386-G-A
• rs80358262
• NM_006432.5:c.133C>T

Variant summary

Our verdict is Pathogenic. The variant received 22 ACMG points: 22P and 0B. PVS1 PS3 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 (★★). ClinVar reports functional evidence for this variant: "SCV000914646: 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" and additional evidence is available in ClinVar. 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
• Publications: 6 publications found

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: ClinGen, Myriad Women’s Health, Labcorp Genetics (formerly Invitae), G2P, Laboratory for Molecular Medicine, Genomics England PanelApp, 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

ACMG classification

Our verdict: Pathogenic. The variant received 22 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PS3: PS3 evidence extracted from ClinVar submissions: SCV000914646: 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).
• 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 Pathogenic/Likely_pathogenic. ClinVar VariationId is 21455.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006432.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NPC2	NM_006432.5	MANE Select	c.133C>T	p.Gln45*	stop_gained	Exon 2 of 5	NP_006423.1	A0A024R6C0
	NPC2	NM_001363688.1		c.133C>T	p.Gln45*	stop_gained	Exon 2 of 4	NP_001350617.1	G3V3E8
	NPC2	NM_001375440.1		c.133C>T	p.Gln45*	stop_gained	Exon 2 of 4	NP_001362369.1	P61916-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NPC2	ENST00000555619.6	TSL:1 MANE Select	c.133C>T	p.Gln45*	stop_gained	Exon 2 of 5	ENSP00000451112.2	P61916-1
	NPC2	ENST00000557510.5	TSL:1	c.133C>T	p.Gln45*	stop_gained	Exon 2 of 4	ENSP00000451206.1	G3V3E8
	NPC2	ENST00000553490.5	TSL:2	c.133C>T	p.Gln45*	stop_gained	Exon 2 of 5	ENSP00000451180.1	G3V3D1

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

African (AFR) AF: 0.00 AC: 0 AN: 33420

American (AMR) AF: 0.00 AC: 0 AN: 43588

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25882

East Asian (EAS) AF: 0.00 AC: 0 AN: 39610

South Asian (SAS) AF: 0.00 AC: 0 AN: 84266

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52962

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5762

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1108274

Other (OTH) AF: 0.00 AC: 0 AN: 60122

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
3	-	-	Niemann-Pick disease, type C2 (4)
1	-	-	Niemann-Pick disease, type C (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
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
PhyloP100		3.1
Vest4		0.96
GERP RS		2.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=3/197	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs80358262; hg19: chr14-74953089;