rs917394

Variant names:

• chr14-74485835-A-G
• rs917394
• NM_006432.5:c.190+494T>C

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 4 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: Myriad Women’s Health, G2P, Genomics England PanelApp, Laboratory for Molecular Medicine, ClinGen, Labcorp Genetics (formerly Invitae), 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: Benign. The variant received -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 rank	MANE	Protein	UniProt
NPC2	NM_006432.5	c.190+494T>C		intron_variant	Intron 2 of 4	ENST00000555619.6	NP_006423.1
NPC2	NM_001363688.1	c.190+494T>C		intron_variant	Intron 2 of 3		NP_001350617.1
NPC2	NM_001375440.1	c.190+494T>C		intron_variant	Intron 2 of 3		NP_001362369.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NPC2	ENST00000555619.6	c.190+494T>C		intron_variant	Intron 2 of 4	1	NM_006432.5	ENSP00000451112.2

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

African (AFR) AF: 0.730 AC: 30284 AN: 41494

American (AMR) AF: 0.680 AC: 10390 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.716 AC: 2486 AN: 3470

East Asian (EAS) AF: 0.419 AC: 2168 AN: 5176

South Asian (SAS) AF: 0.720 AC: 3467 AN: 4818

European-Finnish (FIN) AF: 0.568 AC: 6013 AN: 10584

Middle Eastern (MID) AF: 0.571 AC: 168 AN: 294

European-Non Finnish (NFE) AF: 0.609 AC: 41403 AN: 67996

Other (OTH) AF: 0.630 AC: 1326 AN: 2106

Alfa AF: 0.632 Hom.: 3960

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
PhyloP100		-0.13
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

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