chr18-23544952-C-CCCCG

Position:

• chr18-23544952-C-CCCCG

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BS1 BS2

The NM_000271.5(NPC1):​c.1947+7_1947+8insCGGG variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00131 in 1,425,682 control chromosomes in the GnomAD database, including 12 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00023 (2 hom., cov: 0)
  • Exomes 𝑓: 0.0014 (10 hom.)
• Consequence: NPC1 NM_000271.5 splice_region, intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.0320

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 -16 ACMG points.

• BP6: Variant 18-23544952-C-CCCCG is Benign according to our data. Variant chr18-23544952-C-CCCCG is described in ClinVar as [Likely_benign]. Clinvar id is 284646.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population amr. gnomad4_exome allele frequency = 0.00143 (1830/1281772) while in subpopulation AMR AF= 0.0145 (590/40720). AF 95% confidence interval is 0.0135. There are 10 homozygotes in gnomad4_exome. There are 864 alleles in male gnomad4_exome subpopulation. Median coverage is 25. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NPC1	NM_000271.5	c.1947+7_1947+8insCGGG		splice_region_variant, intron_variant		ENST00000269228.10	NP_000262.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NPC1	ENST00000269228.10	c.1947+7_1947+8insCGGG		splice_region_variant, intron_variant		1	NM_000271.5	ENSP00000269228.4
NPC1	ENST00000591051.1	c.1023+7_1023+8insCGGG		splice_region_variant, intron_variant		2		ENSP00000467636.1
NPC1	ENST00000540608.5	n.1861+7_1861+8insCGGG		splice_region_variant, intron_variant		2

Frequencies

GnomAD3 genomes AF: 0.000229 AC: 33 AN: 143802 Hom.: 2 Cov.: 0

Gnomad AFR AF: 0.0000745

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00137

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000978

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000141

Gnomad OTH AF: 0.000514

GnomAD3 exomes AF: 0.00230 AC: 553 AN: 240878 Hom.: 0 AF XY: 0.00197 AC XY: 258 AN XY: 131214

Gnomad AFR exome AF: 0.000321

Gnomad AMR exome AF: 0.0134

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000333

Gnomad FIN exome AF: 0.0000471

Gnomad NFE exome AF: 0.00105

Gnomad OTH exome AF: 0.00255

GnomAD4 exome AF: 0.00143 AC: 1830 AN: 1281772 Hom.: 10 Cov.: 25 AF XY: 0.00134 AC XY: 864 AN XY: 644492

Gnomad4 AFR exome AF: 0.000287

Gnomad4 AMR exome AF: 0.0145

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000778

Gnomad4 FIN exome AF: 0.000202

Gnomad4 NFE exome AF: 0.00114

Gnomad4 OTH exome AF: 0.00123

GnomAD4 genome AF: 0.000229 AC: 33 AN: 143910 Hom.: 2 Cov.: 0 AF XY: 0.000256 AC XY: 18 AN XY: 70366

Gnomad4 AFR AF: 0.0000743

Gnomad4 AMR AF: 0.00137

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000978

Gnomad4 NFE AF: 0.000141

Gnomad4 OTH AF: 0.000509

Alfa AF: 0.00143 Hom.: 0

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 11, 2015	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

not provided Benign:2

Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -

Niemann-Pick disease, type C1 Benign:2

Likely benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 27, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

NPC1-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 15, 2023

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1555634618; hg19: chr18-21124916;