chr18-23544950-C-CCCCT

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP6BS1BS2

The NM_000271.5(NPC1):​c.1947+9_1947+10insAGGG variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0001 in 1,415,872 control chromosomes in the GnomAD database, including 2 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000097 ( 2 hom., cov: 27)
Exomes 𝑓: 0.00010 ( 0 hom. )

Consequence

NPC1
NM_000271.5 intron

Scores

Not classified

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:2

Conservation

PhyloP100: -0.825

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: Benign. The variant received -9 ACMG points.

BP6
Variant 18-23544950-C-CCCCT is Benign according to our data. Variant chr18-23544950-C-CCCCT is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 499337.We mark this variant Likely_benign, oryginal submission is: [Conflicting_classifications_of_pathogenicity].
BS1
Variant frequency is greater than expected in population amr. GnomAdExome4 allele frequency = 0.000101 (128/1272184) while in subpopulation AMR AF = 0.00284 (122/42966). AF 95% confidence interval is 0.00243. There are 0 homozygotes in GnomAdExome4. There are 49 alleles in the male GnomAdExome4 subpopulation. Median coverage is 26. This position passed quality control check.
BS2
High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
NPC1NM_000271.5 linkc.1947+9_1947+10insAGGG intron_variant Intron 12 of 24 ENST00000269228.10 NP_000262.2

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
NPC1ENST00000269228.10 linkc.1947+9_1947+10insAGGG intron_variant Intron 12 of 24 1 NM_000271.5 ENSP00000269228.4 O15118-1
NPC1ENST00000591051.1 linkc.1023+9_1023+10insAGGG intron_variant Intron 5 of 17 2 ENSP00000467636.1 K7EQ23
NPC1ENST00000540608.5 linkn.1861+9_1861+10insAGGG intron_variant Intron 10 of 15 2

Frequencies

GnomAD3 genomes
AF:
0.0000974
AC:
14
AN:
143688
Hom.:
2
Cov.:
27
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000900
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.000232
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD2 exomes
AF:
0.000508
AC:
124
AN:
244166
AF XY:
0.000324
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00361
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.0000550
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.000101
AC:
128
AN:
1272184
Hom.:
0
Cov.:
26
AF XY:
0.0000765
AC XY:
49
AN XY:
640106
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
31238
American (AMR)
AF:
0.00284
AC:
122
AN:
42966
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
25068
East Asian (EAS)
AF:
0.00
AC:
0
AN:
34646
South Asian (SAS)
AF:
0.0000244
AC:
2
AN:
81848
European-Finnish (FIN)
AF:
0.0000204
AC:
1
AN:
49066
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5458
European-Non Finnish (NFE)
AF:
0.00000105
AC:
1
AN:
948404
Other (OTH)
AF:
0.0000374
AC:
2
AN:
53490
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.448
Heterozygous variant carriers
0
4
8
11
15
19
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
4
8
12
16
20
<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
AF:
0.0000974
AC:
14
AN:
143688
Hom.:
2
Cov.:
27
AF XY:
0.0000712
AC XY:
5
AN XY:
70232
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
40224
American (AMR)
AF:
0.000900
AC:
13
AN:
14440
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3364
East Asian (EAS)
AF:
0.00
AC:
0
AN:
4920
South Asian (SAS)
AF:
0.000232
AC:
1
AN:
4314
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
10008
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
312
European-Non Finnish (NFE)
AF:
0.00
AC:
0
AN:
63304
Other (OTH)
AF:
0.00
AC:
0
AN:
1954
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.645
Heterozygous variant carriers
0
1
1
2
2
3
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome Het
Genome Hom
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
Alfa
AF:
0.00
Hom.:
0

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:1Benign:2
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

Niemann-Pick disease, type C1 Benign:2
Sep 16, 2020
Natera, Inc.
Significance:Likely benign
Review Status:no assertion criteria provided
Collection Method:clinical testing

- -

Dec 07, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

not provided Uncertain:1
Dec 20, 2016
Eurofins Ntd Llc (ga)
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
PhyloP100
-0.82
Mutation Taster
=100/0
polymorphism

Splicing

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

Publications

Other links and lift over

dbSNP: rs772150994; hg19: chr18-21124914; API