18-23544952-C-CCCCCG

Position:

• chr18-23544952-C-CCCCCG

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP6 BS1 BS2

The NM_000271.5(NPC1):​c.1947+7_1947+8insCGGGG variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00081 in 1,427,790 control chromosomes in the GnomAD database, including 16 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0040 (16 hom., cov: 0)
  • Exomes 𝑓: 0.00046 (0 hom.)
• Consequence: NPC1 NM_000271.5 splice_region, intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• 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 -9 ACMG points.

• BP6: Variant 18-23544952-C-CCCCCG is Benign according to our data. Variant chr18-23544952-C-CCCCCG is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 539314.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=1}.
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00397 (570/143536) while in subpopulation AMR AF= 0.0137 (188/13728). AF 95% confidence interval is 0.0121. There are 16 homozygotes in gnomad4. There are 263 alleles in male gnomad4 subpopulation. Median coverage is 0. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 16 AR gene

Transcripts

RefSeq

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

Frequencies

GnomAD3 genomes AF: 0.00397 AC: 569 AN: 143428 Hom.: 16 Cov.: 0

Gnomad AFR AF: 0.00122

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0136

Gnomad ASJ AF: 0.000295

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00184

Gnomad FIN AF: 0.000489

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00493

Gnomad OTH AF: 0.00362

GnomAD3 exomes AF: 0.000673 AC: 162 AN: 240878 Hom.: 0 AF XY: 0.000495 AC XY: 65 AN XY: 131214

Gnomad AFR exome AF: 0.000129

Gnomad AMR exome AF: 0.00388

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000200

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000283

Gnomad OTH exome AF: 0.000850

GnomAD4 exome AF: 0.000457 AC: 587 AN: 1284254 Hom.: 0 Cov.: 25 AF XY: 0.000452 AC XY: 292 AN XY: 645638

Gnomad4 AFR exome AF: 0.000127

Gnomad4 AMR exome AF: 0.00400

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000285

Gnomad4 SAS exome AF: 0.000401

Gnomad4 FIN exome AF: 0.000101

Gnomad4 NFE exome AF: 0.000367

Gnomad4 OTH exome AF: 0.000464

GnomAD4 genome AF: 0.00397 AC: 570 AN: 143536 Hom.: 16 Cov.: 0 AF XY: 0.00375 AC XY: 263 AN XY: 70196

Gnomad4 AFR AF: 0.00121

Gnomad4 AMR AF: 0.0137

Gnomad4 ASJ AF: 0.000295

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00184

Gnomad4 FIN AF: 0.000489

Gnomad4 NFE AF: 0.00492

Gnomad4 OTH AF: 0.00358

Alfa AF: 0.00113 Hom.: 0

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 04, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Dec 01, 2022	NPC1: BP4, BS2 -

Niemann-Pick disease, type C1 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

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;