GeneBe

rs1555634618

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP6_Moderate

The NM_000271.5(NPC1):​c.1947+7_1947+8insT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000777 in 1,287,328 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: not found (cov: 0)
Exomes 𝑓: 7.8e-7 ( 0 hom. )

Consequence

NPC1
NM_000271.5 splice_region, intron

Scores

Not classified

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: -0.0320

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

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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

PM2
Very rare variant in population databases, with high coverage;
BP6
Variant 18-23544952-C-CA is Benign according to our data. Variant chr18-23544952-C-CA is described in ClinVar as Likely_benign. ClinVar VariationId is 1562291.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000271.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected
GeneTranscriptTagsHGVScHGVSpEffectExon RankProteinUniProt
NPC1
NM_000271.5
MANE Select
c.1947+7_1947+8insT
splice_region intron
N/ANP_000262.2

Ensembl Transcripts

Selected
GeneTranscriptTagsHGVScHGVSpEffectExon RankProteinUniProt
NPC1
ENST00000269228.10
TSL:1 MANE Select
c.1947+7_1947+8insT
splice_region intron
N/AENSP00000269228.4
NPC1
ENST00000591051.1
TSL:2
c.1023+7_1023+8insT
splice_region intron
N/AENSP00000467636.1
NPC1
ENST00000540608.5
TSL:2
n.1861+7_1861+8insT
splice_region intron
N/A

Frequencies

GnomAD3 genomes
Cov.:
0
GnomAD4 exome
AF:
7.77e-7
AC:
1
AN:
1287328
Hom.:
0
Cov.:
25
AF XY:
0.00
AC XY:
0
AN XY:
647090
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
31448
American (AMR)
AF:
0.00
AC:
0
AN:
42098
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
25154
East Asian (EAS)
AF:
0.00
AC:
0
AN:
35134
South Asian (SAS)
AF:
0.00
AC:
0
AN:
82458
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
49536
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5452
European-Non Finnish (NFE)
AF:
0.00000104
AC:
1
AN:
962046
Other (OTH)
AF:
0.00
AC:
0
AN:
54002
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.525
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
GnomAD4 genome
Cov.:
0

ClinVar

ClinVar submissions as Germline

Significance:Likely benign
Revision:criteria provided, single submitter
View on ClinVar
Pathogenic
VUS
Benign
Condition
-
-
1
Niemann-Pick disease, type C1 (1)

Computational scores

Source: dbNSFP v4.9

Name
Calibrated prediction
Score
Prediction
PhyloP100
-0.032

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

Other links and lift over

dbSNP: rs1555634618; hg19: chr18-21124916; API