18-23586365-T-G

Position:

• chr18-23586365-T-G

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.-22A>C variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0353 in 1,531,550 control chromosomes in the GnomAD database, including 4,630 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.089 (1424 hom., cov: 33)
  • Exomes 𝑓: 0.029 (3206 hom.)
• Consequence: NPC1 NM_000271.5 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.915

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=-0.76).
• BP6: Variant 18-23586365-T-G is Benign according to our data. Variant chr18-23586365-T-G is described in ClinVar as [Benign]. Clinvar id is 255689.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr18-23586365-T-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.312 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NPC1	NM_000271.5	c.-22A>C		5_prime_UTR_variant	1/25	ENST00000269228.10	NP_000262.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NPC1	ENST00000269228.10	c.-22A>C		5_prime_UTR_variant	1/25	1	NM_000271.5	ENSP00000269228	P1
NPC1	ENST00000540608.5	n.123A>C		non_coding_transcript_exon_variant	1/16	2

Frequencies

GnomAD3 genomes AF: 0.0890 AC: 13542 AN: 152176 Hom.: 1424 Cov.: 33

Gnomad AFR AF: 0.228

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0442

Gnomad ASJ AF: 0.0112

Gnomad EAS AF: 0.325

Gnomad SAS AF: 0.112

Gnomad FIN AF: 0.0139

Gnomad MID AF: 0.0446

Gnomad NFE AF: 0.0125

Gnomad OTH AF: 0.0750

GnomAD3 exomes AF: 0.0681 AC: 8680 AN: 127468 Hom.: 818 AF XY: 0.0661 AC XY: 4625 AN XY: 69964

Gnomad AFR exome AF: 0.220

Gnomad AMR exome AF: 0.0556

Gnomad ASJ exome AF: 0.0120

Gnomad EAS exome AF: 0.321

Gnomad SAS exome AF: 0.0904

Gnomad FIN exome AF: 0.0155

Gnomad NFE exome AF: 0.0107

Gnomad OTH exome AF: 0.0447

GnomAD4 exome AF: 0.0293 AC: 40469 AN: 1379258 Hom.: 3206 Cov.: 31 AF XY: 0.0305 AC XY: 20778 AN XY: 680616

Gnomad4 AFR exome AF: 0.237

Gnomad4 AMR exome AF: 0.0532

Gnomad4 ASJ exome AF: 0.0117

Gnomad4 EAS exome AF: 0.297

Gnomad4 SAS exome AF: 0.0930

Gnomad4 FIN exome AF: 0.0144

Gnomad4 NFE exome AF: 0.00870

Gnomad4 OTH exome AF: 0.0537

GnomAD4 genome AF: 0.0890 AC: 13560 AN: 152292 Hom.: 1424 Cov.: 33 AF XY: 0.0883 AC XY: 6579 AN XY: 74472

Gnomad4 AFR AF: 0.228

Gnomad4 AMR AF: 0.0442

Gnomad4 ASJ AF: 0.0112

Gnomad4 EAS AF: 0.325

Gnomad4 SAS AF: 0.111

Gnomad4 FIN AF: 0.0139

Gnomad4 NFE AF: 0.0125

Gnomad4 OTH AF: 0.0737

Alfa AF: 0.0245 Hom.: 59

Bravo AF: 0.0976

Asia WGS AF: 0.218 AC: 757 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Dec 16, 2015	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Niemann-Pick disease, type C1 Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jun 10, 2021	- -
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. -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.76
CADD	Benign	3.6
DANN	Benign	0.46

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

Other links and lift over

dbSNP: rs2303880; hg19: chr18-21166329;