chr18-23544950-C-A

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_000271.5(NPC1):​c.1947+10G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000096 in 1,415,988 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00020 ( 1 hom., cov: 27)
Exomes 𝑓: 0.000084 ( 2 hom. )

Consequence

NPC1
NM_000271.5 intron

Scores

2

Clinical Significance

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

Conservation

PhyloP100: 0.104
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]

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -9 ACMG points.

BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.85).
BP6
Variant 18-23544950-C-A is Benign according to our data. Variant chr18-23544950-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 495787.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Likely_benign=2}.
BS2
High Homozygotes in GnomAdExome4 at 2 AR gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
NPC1NM_000271.5 linkc.1947+10G>T 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+10G>T intron_variant Intron 12 of 24 1 NM_000271.5 ENSP00000269228.4 O15118-1
NPC1ENST00000591051.1 linkc.1023+10G>T intron_variant Intron 5 of 17 2 ENSP00000467636.1 K7EQ23
NPC1ENST00000540608.5 linkn.1861+10G>T intron_variant Intron 10 of 15 2

Frequencies

GnomAD3 genomes
AF:
0.000188
AC:
27
AN:
143688
Hom.:
1
Cov.:
27
show subpopulations
Gnomad AFR
AF:
0.000323
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000693
Gnomad ASJ
AF:
0.000595
Gnomad EAS
AF:
0.000203
Gnomad SAS
AF:
0.000695
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000948
Gnomad OTH
AF:
0.000512
GnomAD3 exomes
AF:
0.000119
AC:
29
AN:
244166
Hom.:
1
AF XY:
0.000106
AC XY:
14
AN XY:
132590
show subpopulations
Gnomad AFR exome
AF:
0.000516
Gnomad AMR exome
AF:
0.000179
Gnomad ASJ exome
AF:
0.000200
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.000200
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000636
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000841
AC:
107
AN:
1272186
Hom.:
2
Cov.:
26
AF XY:
0.0000922
AC XY:
59
AN XY:
640108
show subpopulations
Gnomad4 AFR exome
AF:
0.000736
Gnomad4 AMR exome
AF:
0.000163
Gnomad4 ASJ exome
AF:
0.000120
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.000110
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000590
Gnomad4 OTH exome
AF:
0.0000935
GnomAD4 genome
AF:
0.000202
AC:
29
AN:
143802
Hom.:
1
Cov.:
27
AF XY:
0.000171
AC XY:
12
AN XY:
70360
show subpopulations
Gnomad4 AFR
AF:
0.000372
Gnomad4 AMR
AF:
0.0000692
Gnomad4 ASJ
AF:
0.000595
Gnomad4 EAS
AF:
0.000204
Gnomad4 SAS
AF:
0.000696
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000948
Gnomad4 OTH
AF:
0.000507
Alfa
AF:
0.0000366
Hom.:
17
Bravo
AF:
0.000227

ClinVar

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

Submissions by phenotype

Niemann-Pick disease, type C1 Uncertain:1Benign:1
Uncertain significance, criteria provided, single submitterclinical testingFulgent Genetics, Fulgent GeneticsOct 31, 2018- -
Likely benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 06, 2025- -
not provided Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingEurofins Ntd Llc (ga)May 21, 2018- -
not specified Benign:1
Likely benign, criteria provided, single submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpDec 12, 2024- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.85
CADD
Benign
0.97
DANN
Benign
0.39

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs71534236; hg19: chr18-21124914; API