rs80358267

chr14-74493247-GC-G

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PVS1 PM2 PP5

The NM_006432.5(NPC2):c.27del(p.Leu10SerfsTer25) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (no stars). Synonymous variant affecting the same amino acid position (i.e. L9L) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: NPC2 NM_006432.5 frameshift
• Clinical Significance: Pathogenic no assertion criteria provided P:1 O:1
• Conservation: PhyloP100: 0.612

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 11 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 46 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 14-74493247-GC-G is Pathogenic according to our data. Variant chr14-74493247-GC-G is described in ClinVar as [Pathogenic]. Clinvar id is 21457.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr14-74493247-GC-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NPC2	NM_006432.5	c.27del	p.Leu10SerfsTer25	frameshift_variant	1/5	ENST00000555619.6
NPC2	NM_001363688.1	c.27del	p.Leu10SerfsTer25	frameshift_variant	1/4
NPC2	NM_001375440.1	c.27del	p.Leu10SerfsTer25	frameshift_variant	1/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NPC2	ENST00000555619.6	c.27del	p.Leu10SerfsTer25	frameshift_variant	1/5	1	NM_006432.5	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1 Other:1

Revision: no assertion criteria provided

Submissions by phenotype

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

Pathogenic, no assertion criteria provided	literature only	OMIM	Nov 01, 2001	- -
not provided, no classification provided	literature only	GeneReviews	-	- -

Computational scores

Source: dbNSFP v4.3

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: rs80358267; hg19: chr14-74959950;