rs61731965

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_000271.5(NPC1):​c.966C>T​(p.Ser322Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00249 in 1,614,068 control chromosomes in the GnomAD database, including 67 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.011 ( 24 hom., cov: 32)
Exomes 𝑓: 0.0016 ( 43 hom. )

Consequence

NPC1
NM_000271.5 synonymous

Scores

2

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: -0.347
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 -21 ACMG points.

BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.53).
BP6
Variant 18-23556603-G-A is Benign according to our data. Variant chr18-23556603-G-A is described in ClinVar as [Benign]. Clinvar id is 326274.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr18-23556603-G-A is described in Lovd as [Likely_benign]. Variant chr18-23556603-G-A is described in Lovd as [Benign].
BP7
Synonymous conserved (PhyloP=-0.347 with no splicing effect.
BS1
Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0114 (1732/152290) while in subpopulation AFR AF= 0.0387 (1606/41550). AF 95% confidence interval is 0.0371. There are 24 homozygotes in gnomad4. There are 815 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
BS2
High Homozygotes in GnomAd4 at 24 AR gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
NPC1NM_000271.5 linkc.966C>T p.Ser322Ser synonymous_variant Exon 8 of 25 ENST00000269228.10 NP_000262.2

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
NPC1ENST00000269228.10 linkc.966C>T p.Ser322Ser synonymous_variant Exon 8 of 25 1 NM_000271.5 ENSP00000269228.4 O15118-1
NPC1ENST00000591051.1 linkc.246C>T p.Ser82Ser synonymous_variant Exon 3 of 18 2 ENSP00000467636.1 K7EQ23
NPC1ENST00000540608.5 linkn.880C>T non_coding_transcript_exon_variant Exon 6 of 16 2

Frequencies

GnomAD3 genomes
AF:
0.0113
AC:
1723
AN:
152172
Hom.:
24
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0386
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00360
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00912
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00316
Gnomad NFE
AF:
0.0000735
Gnomad OTH
AF:
0.00860
GnomAD3 exomes
AF:
0.00376
AC:
939
AN:
249884
Hom.:
11
AF XY:
0.00326
AC XY:
441
AN XY:
135282
show subpopulations
Gnomad AFR exome
AF:
0.0394
Gnomad AMR exome
AF:
0.00174
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00745
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000444
Gnomad OTH exome
AF:
0.00181
GnomAD4 exome
AF:
0.00156
AC:
2282
AN:
1461778
Hom.:
43
Cov.:
32
AF XY:
0.00163
AC XY:
1188
AN XY:
727190
show subpopulations
Gnomad4 AFR exome
AF:
0.0401
Gnomad4 AMR exome
AF:
0.00213
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000504
Gnomad4 SAS exome
AF:
0.00747
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000270
Gnomad4 OTH exome
AF:
0.00270
GnomAD4 genome
AF:
0.0114
AC:
1732
AN:
152290
Hom.:
24
Cov.:
32
AF XY:
0.0109
AC XY:
815
AN XY:
74474
show subpopulations
Gnomad4 AFR
AF:
0.0387
Gnomad4 AMR
AF:
0.00359
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00872
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000735
Gnomad4 OTH
AF:
0.0109
Alfa
AF:
0.000781
Hom.:
0
Bravo
AF:
0.0130
Asia WGS
AF:
0.00462
AC:
16
AN:
3478
EpiCase
AF:
0.00
EpiControl
AF:
0.000119

ClinVar

Significance: Benign
Submissions summary: Benign:7
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Benign:3
-
Genome Diagnostics Laboratory, Amsterdam University Medical Center
Significance: Likely benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Mar 03, 2015
GeneDx
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

-
Breakthrough Genomics, Breakthrough Genomics
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: not provided

- -

Niemann-Pick disease, type C1 Benign:3
Feb 02, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Jan 13, 2018
Illumina Laboratory Services, Illumina
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Sep 16, 2020
Natera, Inc.
Significance: Benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

not specified Benign:1
-
Clinical Genetics, Academic Medical Center
Significance: Benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.53
CADD
Benign
6.3
DANN
Benign
0.74
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7

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: rs61731965; hg19: chr18-21136567; API