rs104894457

Variant names:

• chr14-74480707-G-A
• rs104894457
• NM_006432.5:c.436C>T
• NPC2 p.Gln146*

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PVS1_Moderate PS3 PM2 PP5_Moderate

The NM_006432.5(NPC2):​c.436C>T​(p.Gln146*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,830 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 (★). ClinVar reports functional evidence for this variant: "SCV002766323: "In fibroblasts derived from a homozygous patient, RT-PCR analysis indicated that the variant transcript was not subjected to nonsense mediated decay, however NPC2 protein was not detected by both Western blot and immunocytochemical approahes, suggesting that the variant results in an unstable protein." Verot_2007".

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: NPC2 NM_006432.5 stop_gained
• Clinical Significance: Pathogenic criteria provided, single submitter P:3
• Conservation: PhyloP100: 0.182
• Publications: 5 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: Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), Myriad Women's Health, ClinGen, Ambry Genetics, Genomics England PanelApp, G2P
• 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 10 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most 50 bp of the penultimate exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.0439 CDS is truncated, and there are 1 pathogenic variants in the truncated region.
• PS3: PS3 evidence extracted from ClinVar submissions: SCV002766323: "In fibroblasts derived from a homozygous patient, RT-PCR analysis indicated that the variant transcript was not subjected to nonsense mediated decay, however NPC2 protein was not detected by both Western blot and immunocytochemical approahes, suggesting that the variant results in an unstable protein." Verot_2007
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 14-74480707-G-A is Pathogenic according to our data. Variant chr14-74480707-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 8485.Status of the report is criteria_provided_single_submitter, 1 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.436C>T	p.Gln146*	stop_gained	Exon 4 of 5	NP_006423.1	A0A024R6C0
	NPC2	NM_001363688.1		c.436C>T	p.Gln146*	stop_gained	Exon 4 of 4	NP_001350617.1	G3V3E8
	NPC2	NM_001375440.1		c.364-419C>T		intron	N/A	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.436C>T	p.Gln146*	stop_gained	Exon 4 of 5	ENSP00000451112.2	P61916-1
	NPC2	ENST00000557510.5	TSL:1	c.436C>T	p.Gln146*	stop_gained	Exon 4 of 4	ENSP00000451206.1	G3V3E8
	NPC2	ENST00000553490.5	TSL:2	c.436C>T	p.Gln146*	stop_gained	Exon 4 of 5	ENSP00000451180.1	G3V3D1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460830 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 726810

African (AFR) AF: 0.00 AC: 0 AN: 33460

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26128

East Asian (EAS) AF: 0.00 AC: 0 AN: 39690

South Asian (SAS) AF: 0.00 AC: 0 AN: 86242

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53412

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 9.00e-7 AC: 1 AN: 1111056

Other (OTH) AF: 0.00 AC: 0 AN: 60352

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
2	-	-	Niemann-Pick disease, type C2 (2)
1	-	-	Niemann-Pick disease, type C (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.37	D
BayesDel_noAF	Pathogenic	0.29
CADD	Pathogenic	33
DANN	Benign	0.92
Eigen	Benign	-0.093
Eigen_PC	Benign	-0.44
FATHMM_MKL	Benign	0.30	N
PhyloP100		0.18
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=14/186	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		2.0
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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs104894457;

hg19: chr14-74947410;