Genetic Variant NPC1:c.1947+16_1947+17insGGGGGGGGGGGGGGG (chr18-23544943-A-ACCCCCCCCCCCCCCC) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.

The NM_000271.5(NPC1):c.1947+16_1947+17insGGGGGGGGGGGGGGG variant causes a intron change involving the alteration of a non-conserved nucleotide. It is difficult to determine the true allele frequency of this variant because it is of type INS_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.0 ( 0 hom., cov: 0)

Exomes 𝑓: 0.0000032 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

NPC1
NM_000271.5 intron

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.952

Publications

0 publications found

Variant links:

Genes affected

NPC1 (HGNC:7897): (NPC intracellular cholesterol transporter 1) This gene encodes a large protein that resides in the limiting membrane of endosomes and lysosomes and mediates intracellular cholesterol trafficking via binding of cholesterol to its N-terminal domain. It is predicted to have a cytoplasmic C-terminus, 13 transmembrane domains, and 3 large loops in the lumen of the endosome - the last loop being at the N-terminus. This protein transports low-density lipoproteins to late endosomal/lysosomal compartments where they are hydrolized and released as free cholesterol. Defects in this gene cause Niemann-Pick type C disease, a rare autosomal recessive neurodegenerative disorder characterized by over accumulation of cholesterol and glycosphingolipids in late endosomal/lysosomal compartments.[provided by RefSeq, Aug 2009]

NPC1 Gene-Disease associations (from GenCC):

Niemann-Pick disease, type C1
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: ClinGen, Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), G2P, Genomics England PanelApp, Myriad Women’s Health
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

NPC1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NPC1	NM_000271.5 link	c.1947+16_1947+17insGGGGGGGGGGGGGGG		intron_variant	Intron 12 of 24	ENST00000269228.10	NP_000262.2

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
NPC1	ENST00000269228.10 link	c.1947+16_1947+17insGGGGGGGGGGGGGGG	intron_variant	Intron 12 of 24	1	NM_000271.5	ENSP00000269228.4	O15118-1
NPC1	ENST00000591051.1 link	c.1023+16_1023+17insGGGGGGGGGGGGGGG	intron_variant	Intron 5 of 17	2		ENSP00000467636.1	K7EQ23
NPC1	ENST00000540608.5 link	n.1861+16_1861+17insGGGGGGGGGGGGGGG	intron_variant	Intron 10 of 15	2

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

AN:

104686

Hom.:

Cov.:

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000320

AC:

AN:

937618

Hom.:

Cov.:

AF XY:

0.00000417

AC XY:

AN XY:

479098

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

25944

American (AMR)

AF:

0.00

AC:

AN:

36692

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

21160

East Asian (EAS)

AF:

0.00

AC:

AN:

27016

South Asian (SAS)

AF:

0.00

AC:

AN:

71738

European-Finnish (FIN)

AF:

0.0000248

AC:

AN:

40376

Middle Eastern (MID)

AF:

0.000232

AC:

AN:

4308

European-Non Finnish (NFE)

AF:

0.00000149

AC:

AN:

669412

Other (OTH)

AF:

0.00

AC:

AN:

40972

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.592

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Data not reliable, filtered out with message: AC0;AS_VQSR

AF:

0.00

AC:

AN:

104734

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

49614

African (AFR)

AF:

0.00

AC:

AN:

31430

American (AMR)

AF:

0.00

AC:

AN:

8942

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2802

East Asian (EAS)

AF:

0.00

AC:

AN:

3612

South Asian (SAS)

AF:

0.00

AC:

AN:

3030

European-Finnish (FIN)

AF:

0.00

AC:

AN:

4954

Middle Eastern (MID)

AF:

0.00

AC:

AN:

216

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

47658

Other (OTH)

AF:

0.00

AC:

AN:

1450

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

-0.95

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

18-23544943-ACCCC-ACCCCCCCCCCCCCCCCCCC

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over