chr18-23544946-C-A

Variant names:

• chr18-23544946-C-A
• rs3745024
• NM_000271.5:c.1947+14G>T

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.1947+14G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0217 in 1,329,592 control chromosomes in the GnomAD database, including 3,271 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.022 (381 hom., cov: 27)
  • Exomes 𝑓: 0.022 (2890 hom.)
• Consequence: NPC1 NM_000271.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: -0.765
• Publications: 6 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, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Myriad Women’s Health, Laboratory for Molecular Medicine, G2P
• 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=-0.82).
• BP6: Variant 18-23544946-C-A is Benign according to our data. Variant chr18-23544946-C-A is described in ClinVar as Benign. ClinVar VariationId is 92704.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.303 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000271.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NPC1	NM_000271.5	MANE Select	c.1947+14G>T		intron	N/A	NP_000262.2	O15118-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NPC1	ENST00000269228.10	TSL:1 MANE Select	c.1947+14G>T		intron	N/A	ENSP00000269228.4	O15118-1
	NPC1	ENST00000897526.1		c.1998+14G>T		intron	N/A	ENSP00000567585.1
	NPC1	ENST00000926494.1		c.1947+14G>T		intron	N/A	ENSP00000596553.1

Frequencies

GnomAD3 genomes AF: 0.0216 AC: 2931 AN: 135898 Hom.: 383 Cov.: 27

Gnomad AFR AF: 0.00511

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0180

Gnomad ASJ AF: 0.00726

Gnomad EAS AF: 0.317

Gnomad SAS AF: 0.0878

Gnomad FIN AF: 0.0137

Gnomad MID AF: 0.0233

Gnomad NFE AF: 0.00878

Gnomad OTH AF: 0.0214

GnomAD2 exomes AF: 0.0449 AC: 10474 AN: 233216 AF XY: 0.0436

Gnomad AFR exome AF: 0.00465

Gnomad AMR exome AF: 0.0491

Gnomad ASJ exome AF: 0.00771

Gnomad EAS exome AF: 0.305

Gnomad FIN exome AF: 0.0151

Gnomad NFE exome AF: 0.00826

Gnomad OTH exome AF: 0.0286

GnomAD4 exome AF: 0.0218 AC: 25990 AN: 1193600 Hom.: 2890 Cov.: 24 AF XY: 0.0233 AC XY: 14066 AN XY: 602878

African (AFR) AF: 0.00314 AC: 95 AN: 30276

American (AMR) AF: 0.0439 AC: 1828 AN: 41608

Ashkenazi Jewish (ASJ) AF: 0.00797 AC: 196 AN: 24580

East Asian (EAS) AF: 0.328 AC: 10548 AN: 32156

South Asian (SAS) AF: 0.0706 AC: 5594 AN: 79200

European-Finnish (FIN) AF: 0.0153 AC: 726 AN: 47572

Middle Eastern (MID) AF: 0.0198 AC: 104 AN: 5262

European-Non Finnish (NFE) AF: 0.00598 AC: 5275 AN: 882278

Other (OTH) AF: 0.0321 AC: 1624 AN: 50668

GnomAD4 genome AF: 0.0215 AC: 2924 AN: 135992 Hom.: 381 Cov.: 27 AF XY: 0.0236 AC XY: 1572 AN XY: 66574

African (AFR) AF: 0.00509 AC: 187 AN: 36722

American (AMR) AF: 0.0180 AC: 249 AN: 13826

Ashkenazi Jewish (ASJ) AF: 0.00726 AC: 24 AN: 3304

East Asian (EAS) AF: 0.317 AC: 1391 AN: 4392

South Asian (SAS) AF: 0.0879 AC: 359 AN: 4086

European-Finnish (FIN) AF: 0.0137 AC: 134 AN: 9770

Middle Eastern (MID) AF: 0.0214 AC: 6 AN: 280

European-Non Finnish (NFE) AF: 0.00879 AC: 535 AN: 60898

Other (OTH) AF: 0.0206 AC: 39 AN: 1892

Alfa AF: 0.0119 Hom.: 51

Bravo AF: 0.0201

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	Niemann-Pick disease, type C1 (5)
-	-	5	not specified (5)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	1.1
DANN	Benign	0.39
PhyloP100		-0.77
Mutation Taster		=100/0	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: rs3745024; hg19: chr18-21124910;