18-23586365-T-G

Variant names:

• chr18-23586365-T-G
• rs2303880
• NM_000271.5:c.-22A>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000271.5(NPC1):​c.-22A>C variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0353 in 1,531,550 control chromosomes in the GnomAD database, including 4,630 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.089 (1424 hom., cov: 33)
  • Exomes 𝑓: 0.029 (3206 hom.)
• Consequence: NPC1 NM_000271.5 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.915
• Publications: 10 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]

NPC1 Gene-Disease associations (from GenCC):

• Niemann-Pick disease, type C1

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: ClinGen, Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), G2P, Genomics England PanelApp, Myriad Women’s Health
• Niemann-Pick disease type C, adult neurologic onset

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• Niemann-Pick disease type C, juvenile neurologic onset

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• Niemann-Pick disease type C, late infantile neurologic onset

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• Niemann-Pick disease type C, severe early infantile neurologic onset

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• Niemann-Pick disease type C, severe perinatal form

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.76).
• BP6: Variant 18-23586365-T-G is Benign according to our data. Variant chr18-23586365-T-G is described in ClinVar as Benign. ClinVar VariationId is 255689.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.312 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NPC1	NM_000271.5	c.-22A>C		5_prime_UTR_variant	Exon 1 of 25	ENST00000269228.10	NP_000262.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NPC1	ENST00000269228.10	c.-22A>C		5_prime_UTR_variant	Exon 1 of 25	1	NM_000271.5	ENSP00000269228.4
NPC1	ENST00000540608.5	n.123A>C		non_coding_transcript_exon_variant	Exon 1 of 16	2

Frequencies

GnomAD3 genomes AF: 0.0890 AC: 13542 AN: 152176 Hom.: 1424 Cov.: 33

Gnomad AFR AF: 0.228

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0442

Gnomad ASJ AF: 0.0112

Gnomad EAS AF: 0.325

Gnomad SAS AF: 0.112

Gnomad FIN AF: 0.0139

Gnomad MID AF: 0.0446

Gnomad NFE AF: 0.0125

Gnomad OTH AF: 0.0750

GnomAD2 exomes AF: 0.0681 AC: 8680 AN: 127468 AF XY: 0.0661

Gnomad AFR exome AF: 0.220

Gnomad AMR exome AF: 0.0556

Gnomad ASJ exome AF: 0.0120

Gnomad EAS exome AF: 0.321

Gnomad FIN exome AF: 0.0155

Gnomad NFE exome AF: 0.0107

Gnomad OTH exome AF: 0.0447

GnomAD4 exome AF: 0.0293 AC: 40469 AN: 1379258 Hom.: 3206 Cov.: 31 AF XY: 0.0305 AC XY: 20778 AN XY: 680616

African (AFR) AF: 0.237 AC: 7340 AN: 30930

American (AMR) AF: 0.0532 AC: 1889 AN: 35524

Ashkenazi Jewish (ASJ) AF: 0.0117 AC: 292 AN: 25030

East Asian (EAS) AF: 0.297 AC: 10475 AN: 35308

South Asian (SAS) AF: 0.0930 AC: 7323 AN: 78778

European-Finnish (FIN) AF: 0.0144 AC: 497 AN: 34494

Middle Eastern (MID) AF: 0.0466 AC: 195 AN: 4188

European-Non Finnish (NFE) AF: 0.00870 AC: 9369 AN: 1077432

Other (OTH) AF: 0.0537 AC: 3089 AN: 57574

GnomAD4 genome AF: 0.0890 AC: 13560 AN: 152292 Hom.: 1424 Cov.: 33 AF XY: 0.0883 AC XY: 6579 AN XY: 74472

African (AFR) AF: 0.228 AC: 9467 AN: 41560

American (AMR) AF: 0.0442 AC: 676 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.0112 AC: 39 AN: 3468

East Asian (EAS) AF: 0.325 AC: 1678 AN: 5168

South Asian (SAS) AF: 0.111 AC: 537 AN: 4830

European-Finnish (FIN) AF: 0.0139 AC: 148 AN: 10628

Middle Eastern (MID) AF: 0.0411 AC: 12 AN: 292

European-Non Finnish (NFE) AF: 0.0125 AC: 847 AN: 68012

Other (OTH) AF: 0.0737 AC: 156 AN: 2116

Alfa AF: 0.0323 Hom.: 68

Bravo AF: 0.0976

Asia WGS AF: 0.218 AC: 757 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Dec 16, 2015

Mayo Clinic Laboratories, Mayo Clinic

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Niemann-Pick disease, type C1 Benign:2

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Jun 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.76
CADD	Benign	3.6
DANN	Benign	0.46
PhyloP100		-0.92
PromoterAI		-0.12	Neutral
Mutation Taster		=300/0	polymorphism (auto)

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: rs2303880; hg19: chr18-21166329;