18-23544943-ACCCC-ACCCCCCCCCC

Variant names:

• chr18-23544943-A-ACCCCCC
• rs3837910
• NM_000271.5:c.1947+11_1947+16dupGGGGGG

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP6_Moderate BS1 BS2

The NM_000271.5(NPC1):​c.1947+11_1947+16dupGGGGGG variant causes a intron change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0028 (17 hom., cov: 0)
  • Exomes 𝑓: 0.00090 (27 hom.)
• Consequence: NPC1 NM_000271.5 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.952

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 -10 ACMG points.

• BP6: Variant 18-23544943-A-ACCCCCC is Benign according to our data. Variant chr18-23544943-A-ACCCCCC is described in ClinVar as [Likely_benign]. Clinvar id is 1574507.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00285 (298/104564) while in subpopulation EAS AF= 0.00836 (30/3590). AF 95% confidence interval is 0.00601. There are 17 homozygotes in gnomad4. There are 140 alleles in male gnomad4 subpopulation. Median coverage is 0. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 17 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NPC1	NM_000271.5	c.1947+11_1947+16dupGGGGGG		intron_variant	Intron 12 of 24	ENST00000269228.10	NP_000262.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NPC1	ENST00000269228.10	c.1947+16_1947+17insGGGGGG		intron_variant	Intron 12 of 24	1	NM_000271.5	ENSP00000269228.4
NPC1	ENST00000591051.1	c.1023+16_1023+17insGGGGGG		intron_variant	Intron 5 of 17	2		ENSP00000467636.1
NPC1	ENST00000540608.5	n.1861+16_1861+17insGGGGGG		intron_variant	Intron 10 of 15	2

Frequencies

GnomAD3 genomes AF: 0.00286 AC: 299 AN: 104516 Hom.: 17 Cov.: 0

Gnomad AFR AF: 0.00230

Gnomad AMI AF: 0.00469

Gnomad AMR AF: 0.00224

Gnomad ASJ AF: 0.00286

Gnomad EAS AF: 0.00861

Gnomad SAS AF: 0.00231

Gnomad FIN AF: 0.00121

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00313

Gnomad OTH AF: 0.00208

GnomAD4 exome AF: 0.000897 AC: 840 AN: 936310 Hom.: 27 Cov.: 19 AF XY: 0.000945 AC XY: 452 AN XY: 478426

Gnomad4 AFR exome AF: 0.000270

Gnomad4 AMR exome AF: 0.00106

Gnomad4 ASJ exome AF: 0.000331

Gnomad4 EAS exome AF: 0.00149

Gnomad4 SAS exome AF: 0.00211

Gnomad4 FIN exome AF: 0.00415

Gnomad4 NFE exome AF: 0.000591

Gnomad4 OTH exome AF: 0.000807

GnomAD4 genome AF: 0.00285 AC: 298 AN: 104564 Hom.: 17 Cov.: 0 AF XY: 0.00283 AC XY: 140 AN XY: 49528

Gnomad4 AFR AF: 0.00229

Gnomad4 AMR AF: 0.00224

Gnomad4 ASJ AF: 0.00286

Gnomad4 EAS AF: 0.00836

Gnomad4 SAS AF: 0.00232

Gnomad4 FIN AF: 0.00121

Gnomad4 NFE AF: 0.00313

Gnomad4 OTH AF: 0.00207

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Niemann-Pick disease, type C1 Benign:1

Jan 28, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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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: rs3837910; hg19: chr18-21124907;