chr18-23544950-C-CCCCCG

Position:

• chr18-23544950-C-CCCCCG

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP6_Moderate

The NM_000271.5(NPC1):​c.1947+9_1947+10insCGGGG variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000742 in 1,415,932 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00015 (1 hom., cov: 27)
  • Exomes 𝑓: 0.000066 (0 hom.)
• Consequence: NPC1 NM_000271.5 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.825

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP6: Variant 18-23544950-C-CCCCCG is Benign according to our data. Variant chr18-23544950-C-CCCCCG is described in ClinVar as [Likely_benign]. Clinvar id is 720210.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NPC1	NM_000271.5	c.1947+9_1947+10insCGGGG		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+9_1947+10insCGGGG		intron_variant		1	NM_000271.5	ENSP00000269228	P1
NPC1	ENST00000591051.1	c.1025+9_1025+10insCGGGG		intron_variant		2		ENSP00000467636
NPC1	ENST00000540608.5	n.1861+9_1861+10insCGGGG		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes AF: 0.000146 AC: 21 AN: 143688 Hom.: 1 Cov.: 27

Gnomad AFR AF: 0.0000497

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000762

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000464

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000948

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000660 AC: 84 AN: 1272130 Hom.: 0 Cov.: 26 AF XY: 0.0000703 AC XY: 45 AN XY: 640080

Gnomad4 AFR exome AF: 0.0000320

Gnomad4 AMR exome AF: 0.000116

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000577

Gnomad4 SAS exome AF: 0.0000611

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000728

Gnomad4 OTH exome AF: 0.0000374

GnomAD4 genome AF: 0.000146 AC: 21 AN: 143802 Hom.: 1 Cov.: 27 AF XY: 0.000199 AC XY: 14 AN XY: 70362

Gnomad4 AFR AF: 0.0000496

Gnomad4 AMR AF: 0.000761

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000464

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000948

Gnomad4 OTH AF: 0.00

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Niemann-Pick disease, type C1 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 19, 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: rs772150994; hg19: chr18-21124914;