18-23531484-G-C

Variant names:

• chr18-23531484-G-C
• rs1227797863
• NM_000271.5:c.*718C>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_000271.5(NPC1):​c.*718C>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000463 in 1,295,892 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000046 (0 hom.)
• Consequence: NPC1 NM_000271.5 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.218
• Publications: 0 publications found

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]

RMC1 (HGNC:24326): (regulator of MON1-CCZ1) This gene encodes a colon cancer associated protein. [provided by RefSeq, Jan 2013]

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.65).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NPC1	NM_000271.5	c.*718C>G		3_prime_UTR_variant	Exon 25 of 25	ENST00000269228.10	NP_000262.2
RMC1	NM_013326.5	c.1895-141G>C		intron_variant	Intron 19 of 19	ENST00000269221.8	NP_037458.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NPC1	ENST00000269228.10	c.*718C>G		3_prime_UTR_variant	Exon 25 of 25	1	NM_000271.5	ENSP00000269228.4
RMC1	ENST00000269221.8	c.1895-141G>C		intron_variant	Intron 19 of 19	1	NM_013326.5	ENSP00000269221.2
RMC1	ENST00000590868.5	c.1751-141G>C		intron_variant	Intron 17 of 17	2		ENSP00000467007.1
RMC1	ENST00000615148.5	c.1771-141G>C		intron_variant	Intron 19 of 19	5		ENSP00000482573.2
RMC1	ENST00000589215.5	n.*1428-141G>C		intron_variant	Intron 18 of 18	2		ENSP00000467852.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000463 AC: 6 AN: 1295892 Hom.: 0 Cov.: 28 AF XY: 0.00000790 AC XY: 5 AN XY: 632776

African (AFR) AF: 0.00 AC: 0 AN: 28322

American (AMR) AF: 0.00 AC: 0 AN: 20912

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19176

East Asian (EAS) AF: 0.00 AC: 0 AN: 35370

South Asian (SAS) AF: 0.00 AC: 0 AN: 61950

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 33990

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5194

European-Non Finnish (NFE) AF: 0.00000578 AC: 6 AN: 1037264

Other (OTH) AF: 0.00 AC: 0 AN: 53714

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.65
CADD	Benign	0.62
DANN	Benign	0.78
PhyloP100		0.22
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1227797863; hg19: chr18-21111448;