18-23544952-C-CCCG

Position:

• chr18-23544952-C-CCCG

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+8insCGG variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000404 in 1,428,746 control chromosomes in the GnomAD database, including 4 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.000042 (0 hom., cov: 0)
  • Exomes 𝑓: 0.00044 (4 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-CCCG is Benign according to our data. Variant chr18-23544952-C-CCCG is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 594945.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Benign=1}.
• BS1: Variant frequency is greater than expected in population amr. gnomad4_exome allele frequency = 0.000444 (571/1284822) while in subpopulation AMR AF= 0.00437 (181/41384). AF 95% confidence interval is 0.00385. There are 4 homozygotes in gnomad4_exome. There are 300 alleles in male gnomad4_exome subpopulation. Median coverage is 25. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 4 AR gene

Transcripts

RefSeq

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

Frequencies

GnomAD3 genomes AF: 0.0000417 AC: 6 AN: 143816 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.0000248

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000289

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000157

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000884 AC: 213 AN: 240878 Hom.: 2 AF XY: 0.000747 AC XY: 98 AN XY: 131214

Gnomad AFR exome AF: 0.0000643

Gnomad AMR exome AF: 0.00470

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000133

Gnomad FIN exome AF: 0.0000942

Gnomad NFE exome AF: 0.000539

Gnomad OTH exome AF: 0.000680

GnomAD4 exome AF: 0.000444 AC: 571 AN: 1284822 Hom.: 4 Cov.: 25 AF XY: 0.000465 AC XY: 300 AN XY: 645804

Gnomad4 AFR exome AF: 0.000159

Gnomad4 AMR exome AF: 0.00437

Gnomad4 ASJ exome AF: 0.0000398

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000219

Gnomad4 FIN exome AF: 0.0000202

Gnomad4 NFE exome AF: 0.000357

Gnomad4 OTH exome AF: 0.000390

GnomAD4 genome AF: 0.0000417 AC: 6 AN: 143924 Hom.: 0 Cov.: 0 AF XY: 0.0000142 AC XY: 1 AN XY: 70376

Gnomad4 AFR AF: 0.0000248

Gnomad4 AMR AF: 0.000289

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000157

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000402 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Apr 25, 2018

- -

NPC1-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 10, 2021

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

Niemann-Pick disease, type C1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 28, 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;