18-23544943-ACCCC-ACCCCCCCCCCCCCCCC

Variant names:

• chr18-23544943-A-ACCCCCCCCCCCC
• rs3837910
• NM_000271.5:c.1947+16_1947+17insGGGGGGGGGGGG

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2

The NM_000271.5(NPC1):​c.1947+16_1947+17insGGGGGGGGGGGG variant causes a intron change involving the alteration of a non-conserved nucleotide. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.00025 (3 hom., cov: 0)
  • Exomes 𝑓: 0.000015 (0 hom.)
• Consequence: NPC1 NM_000271.5 intron
• Clinical Significance: Not reported in ClinVar
• 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 Likely_benign. Variant got -4 ACMG points.

• BS2: High Homozygotes in GnomAd4 at 3 AR gene

Transcripts

RefSeq

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

Frequencies

GnomAD3 genomes AF: 0.000248 AC: 26 AN: 104680 Hom.: 3 Cov.: 0

Gnomad AFR AF: 0.0000638

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000276

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000606

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000420

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000149 AC: 14 AN: 937576 Hom.: 0 Cov.: 19 AF XY: 0.0000167 AC XY: 8 AN XY: 479080

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000273

Gnomad4 ASJ exome AF: 0.0000473

Gnomad4 EAS exome AF: 0.0000370

Gnomad4 SAS exome AF: 0.0000279

Gnomad4 FIN exome AF: 0.0000248

Gnomad4 NFE exome AF: 0.0000105

Gnomad4 OTH exome AF: 0.0000244

GnomAD4 genome AF: 0.000248 AC: 26 AN: 104728 Hom.: 3 Cov.: 0 AF XY: 0.000161 AC XY: 8 AN XY: 49612

Gnomad4 AFR AF: 0.0000636

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000277

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000606

Gnomad4 NFE AF: 0.000420

Gnomad4 OTH AF: 0.00

ClinVar

Not reported in ClinVar

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;