14-74493247-GC-G

Position:

• chr14-74493247-GC-G

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PVS1_Strong 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).

• 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 Likely_pathogenic. Variant got 7 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 14 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	Protein	UniProt
NPC2	NM_006432.5	c.27del	p.Leu10SerfsTer25	frameshift_variant	1/5	ENST00000555619.6	NP_006423.1
NPC2	NM_001363688.1	c.27del	p.Leu10SerfsTer25	frameshift_variant	1/4		NP_001350617.1
NPC2	NM_001375440.1	c.27del	p.Leu10SerfsTer25	frameshift_variant	1/4		NP_001362369.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NPC2	ENST00000555619.6	c.27del	p.Leu10SerfsTer25	frameshift_variant	1/5	1	NM_006432.5	ENSP00000451112	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;