rs73392120

Positions:

• chr18-23541062-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000271.5(NPC1):​c.2514+6C>T variant causes a splice donor region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00257 in 1,613,974 control chromosomes in the GnomAD database, including 96 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.014 (36 hom., cov: 32)
  • Exomes 𝑓: 0.0014 (60 hom.)
• Consequence: NPC1 NM_000271.5 splice_donor_region, intron
• Scores: Splicing: ADA: 0.00002474
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.104

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 18-23541062-G-A is Benign according to our data. Variant chr18-23541062-G-A is described in ClinVar as [Benign]. Clinvar id is 92707.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr18-23541062-G-A is described in Lovd as [Benign]. Variant chr18-23541062-G-A is described in Lovd as [Likely_benign].
• BA1: GnomAdExome4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0502 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NPC1	NM_000271.5	c.2514+6C>T		splice_donor_region_variant, intron_variant		ENST00000269228.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NPC1	ENST00000269228.10	c.2514+6C>T		splice_donor_region_variant, intron_variant		1	NM_000271.5	P1
NPC1	ENST00000591051.1	c.1592+6C>T		splice_donor_region_variant, intron_variant		2
NPC1	ENST00000540608.5	n.2428+6C>T		splice_donor_region_variant, intron_variant, non_coding_transcript_variant		2
NPC1	ENST00000586718.1	n.305+6C>T		splice_donor_region_variant, intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.0137 AC: 2084 AN: 152068 Hom.: 36 Cov.: 32

Gnomad AFR AF: 0.0485

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00393

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000578

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00528

GnomAD3 exomes AF: 0.00388 AC: 975 AN: 251426 Hom.: 22 AF XY: 0.00269 AC XY: 366 AN XY: 135882

Gnomad AFR exome AF: 0.0542

Gnomad AMR exome AF: 0.00197

Gnomad ASJ exome AF: 0.0000992

Gnomad EAS exome AF: 0.000652

Gnomad SAS exome AF: 0.0000653

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000528

Gnomad OTH exome AF: 0.000815

GnomAD4 exome AF: 0.00142 AC: 2070 AN: 1461786 Hom.: 60 Cov.: 32 AF XY: 0.00116 AC XY: 846 AN XY: 727200

Gnomad4 AFR exome AF: 0.0523

Gnomad4 AMR exome AF: 0.00219

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.000277

Gnomad4 SAS exome AF: 0.0000927

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000225

Gnomad4 OTH exome AF: 0.00273

GnomAD4 genome AF: 0.0137 AC: 2085 AN: 152188 Hom.: 36 Cov.: 32 AF XY: 0.0126 AC XY: 936 AN XY: 74394

Gnomad4 AFR AF: 0.0484

Gnomad4 AMR AF: 0.00392

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000579

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00522

Alfa AF: 0.00742 Hom.: 14

Bravo AF: 0.0155

Asia WGS AF: 0.00260 AC: 10 AN: 3478

EpiCase AF: 0.000164

EpiControl AF: 0.00

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Niemann-Pick disease, type C1 Benign:3

Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	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. -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 29, 2013	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 07, 2018	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	0.22
DANN	Benign	0.62
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000025
dbscSNV1_RF	Benign	0.0
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

Other links and lift over

dbSNP: rs73392120; hg19: chr18-21121026;