rs2435307

Positions:

• chr18-23547946-C-T

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.1757+60G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.481 in 992,996 control chromosomes in the GnomAD database, including 117,190 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.47 (17050 hom., cov: 32)
  • Exomes 𝑓: 0.48 (100140 hom.)
• Consequence: NPC1 NM_000271.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.103

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 18-23547946-C-T is Benign according to our data. Variant chr18-23547946-C-T is described in ClinVar as [Benign]. Clinvar id is 1172933.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr18-23547946-C-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.584 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NPC1	NM_000271.5	c.1757+60G>A		intron_variant		ENST00000269228.10	NP_000262.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NPC1	ENST00000269228.10	c.1757+60G>A		intron_variant		1	NM_000271.5	ENSP00000269228.4
NPC1	ENST00000591051.1	c.834-2797G>A		intron_variant		2		ENSP00000467636.1
NPC1	ENST00000540608.5	n.1671+60G>A		intron_variant		2

Frequencies

GnomAD3 genomes AF: 0.470 AC: 71332 AN: 151844 Hom.: 17030 Cov.: 32

Gnomad AFR AF: 0.418

Gnomad AMI AF: 0.423

Gnomad AMR AF: 0.566

Gnomad ASJ AF: 0.303

Gnomad EAS AF: 0.602

Gnomad SAS AF: 0.468

Gnomad FIN AF: 0.519

Gnomad MID AF: 0.299

Gnomad NFE AF: 0.473

Gnomad OTH AF: 0.437

GnomAD4 exome AF: 0.483 AC: 406467 AN: 841034 Hom.: 100140 AF XY: 0.479 AC XY: 212892 AN XY: 443990

Gnomad4 AFR exome AF: 0.416

Gnomad4 AMR exome AF: 0.644

Gnomad4 ASJ exome AF: 0.297

Gnomad4 EAS exome AF: 0.634

Gnomad4 SAS exome AF: 0.478

Gnomad4 FIN exome AF: 0.496

Gnomad4 NFE exome AF: 0.473

Gnomad4 OTH exome AF: 0.460

GnomAD4 genome AF: 0.470 AC: 71416 AN: 151962 Hom.: 17050 Cov.: 32 AF XY: 0.473 AC XY: 35171 AN XY: 74284

Gnomad4 AFR AF: 0.418

Gnomad4 AMR AF: 0.567

Gnomad4 ASJ AF: 0.303

Gnomad4 EAS AF: 0.601

Gnomad4 SAS AF: 0.470

Gnomad4 FIN AF: 0.519

Gnomad4 NFE AF: 0.473

Gnomad4 OTH AF: 0.442

Alfa AF: 0.464 Hom.: 17099

Bravo AF: 0.476

Asia WGS AF: 0.541 AC: 1880 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Niemann-Pick disease, type C1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jun 10, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	2.0
DANN	Benign	0.36

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: rs2435307; hg19: chr18-21127910; COSMIC: COSV52577265; COSMIC: COSV52577265;