rs917394

chr14-74485835-A-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_006432.5(NPC2):c.190+494T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.647 in 152,126 control chromosomes in the GnomAD database, including 32,300 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.65 (32300 hom., cov: 32)
• Consequence: NPC2 NM_006432.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.128

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 Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.71).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.723 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NPC2	NM_006432.5	c.190+494T>C		intron_variant		ENST00000555619.6
NPC2	NM_001363688.1	c.190+494T>C		intron_variant
NPC2	NM_001375440.1	c.190+494T>C		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NPC2	ENST00000555619.6	c.190+494T>C		intron_variant		1	NM_006432.5	P4

Frequencies

GnomAD3 genomes AF: 0.647 AC: 98300 AN: 152008 Hom.: 32259 Cov.: 32

Gnomad AFR AF: 0.730

Gnomad AMI AF: 0.766

Gnomad AMR AF: 0.680

Gnomad ASJ AF: 0.716

Gnomad EAS AF: 0.418

Gnomad SAS AF: 0.721

Gnomad FIN AF: 0.568

Gnomad MID AF: 0.576

Gnomad NFE AF: 0.609

Gnomad OTH AF: 0.628

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.647 AC: 98402 AN: 152126 Hom.: 32300 Cov.: 32 AF XY: 0.648 AC XY: 48198 AN XY: 74374

Gnomad4 AFR AF: 0.730

Gnomad4 AMR AF: 0.680

Gnomad4 ASJ AF: 0.716

Gnomad4 EAS AF: 0.419

Gnomad4 SAS AF: 0.720

Gnomad4 FIN AF: 0.568

Gnomad4 NFE AF: 0.609

Gnomad4 OTH AF: 0.630

Alfa AF: 0.628 Hom.: 3748

Bravo AF: 0.655

Asia WGS AF: 0.614 AC: 2136 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.71
Cadd	Benign	11
Dann	Benign	0.89

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: rs917394; hg19: chr14-74952538; COSMIC: COSV53143564; COSMIC: COSV53143564;