18-23532242-C-T

Variant names:

• chr18-23532242-C-T
• rs1805084
• NM_000271.5:c.3797G>A

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BA1

The NM_000271.5(NPC1):​c.3797G>A​(p.Arg1266Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0497 in 1,614,046 control chromosomes in the GnomAD database, including 4,326 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1266L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.10 (1375 hom., cov: 32)
  • Exomes 𝑓: 0.044 (2951 hom.)
• Consequence: NPC1 NM_000271.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:13 O:1
• Conservation: PhyloP100: 2.23
• Publications: 33 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 -19 ACMG points.

• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 171 curated pathogenic missense variants (we use a threshold of 10). The gene has 18 curated benign missense variants. Gene score misZ: 1.0917 (below the threshold of 3.09). Trascript score misZ: 1.706 (below the threshold of 3.09). GenCC associations: The gene is linked to Niemann-Pick disease type C, severe early infantile neurologic onset, Niemann-Pick disease type C, late infantile neurologic onset, Niemann-Pick disease type C, juvenile neurologic onset, Niemann-Pick disease type C, severe perinatal form, Niemann-Pick disease type C, adult neurologic onset, Niemann-Pick disease, type C1.
• BP4: Computational evidence support a benign effect (MetaRNN=0.0023930073).
• BP6: Variant 18-23532242-C-T is Benign according to our data. Variant chr18-23532242-C-T is described in ClinVar as Benign. ClinVar VariationId is 21140.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.232 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.3797G>A	p.Arg1266Gln	missense	Exon 25 of 25	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.3797G>A	p.Arg1266Gln	missense	Exon 25 of 25	ENSP00000269228.4	O15118-1
	NPC1	ENST00000593280.2	TSL:1	c.85+1113G>A		intron	N/A	ENSP00000467150.1	K7ENZ0
	NPC1	ENST00000897526.1		c.3848G>A	p.Arg1283Gln	missense	Exon 25 of 25	ENSP00000567585.1

Frequencies

GnomAD3 genomes AF: 0.101 AC: 15335 AN: 152048 Hom.: 1373 Cov.: 32

Gnomad AFR AF: 0.236

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.108

Gnomad ASJ AF: 0.0305

Gnomad EAS AF: 0.196

Gnomad SAS AF: 0.0788

Gnomad FIN AF: 0.00943

Gnomad MID AF: 0.0538

Gnomad NFE AF: 0.0310

Gnomad OTH AF: 0.104

GnomAD2 exomes AF: 0.0723 AC: 18192 AN: 251450 AF XY: 0.0663

Gnomad AFR exome AF: 0.246

Gnomad AMR exome AF: 0.112

Gnomad ASJ exome AF: 0.0258

Gnomad EAS exome AF: 0.206

Gnomad FIN exome AF: 0.0112

Gnomad NFE exome AF: 0.0312

Gnomad OTH exome AF: 0.0625

GnomAD4 exome AF: 0.0443 AC: 64795 AN: 1461880 Hom.: 2951 Cov.: 32 AF XY: 0.0441 AC XY: 32094 AN XY: 727242

African (AFR) AF: 0.247 AC: 8268 AN: 33480

American (AMR) AF: 0.111 AC: 4947 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0248 AC: 648 AN: 26136

East Asian (EAS) AF: 0.179 AC: 7103 AN: 39700

South Asian (SAS) AF: 0.0679 AC: 5857 AN: 86258

European-Finnish (FIN) AF: 0.0111 AC: 595 AN: 53420

Middle Eastern (MID) AF: 0.0850 AC: 490 AN: 5768

European-Non Finnish (NFE) AF: 0.0299 AC: 33285 AN: 1111998

Other (OTH) AF: 0.0596 AC: 3602 AN: 60396

GnomAD4 genome AF: 0.101 AC: 15379 AN: 152166 Hom.: 1375 Cov.: 32 AF XY: 0.103 AC XY: 7627 AN XY: 74396

African (AFR) AF: 0.236 AC: 9795 AN: 41500

American (AMR) AF: 0.108 AC: 1647 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.0305 AC: 106 AN: 3472

East Asian (EAS) AF: 0.196 AC: 1008 AN: 5156

South Asian (SAS) AF: 0.0789 AC: 380 AN: 4816

European-Finnish (FIN) AF: 0.00943 AC: 100 AN: 10602

Middle Eastern (MID) AF: 0.0544 AC: 16 AN: 294

European-Non Finnish (NFE) AF: 0.0310 AC: 2108 AN: 68014

Other (OTH) AF: 0.104 AC: 219 AN: 2114

Alfa AF: 0.0541 Hom.: 2035

Bravo AF: 0.117

TwinsUK AF: 0.0291 AC: 108

ALSPAC AF: 0.0317 AC: 122

ESP6500AA AF: 0.231 AC: 1017

ESP6500EA AF: 0.0300 AC: 258

ExAC AF: 0.0731 AC: 8872

Asia WGS AF: 0.126 AC: 437 AN: 3478

EpiCase AF: 0.0353

EpiControl AF: 0.0372

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	Niemann-Pick disease, type C1 (7)
-	-	4	not specified (4)
-	-	3	not provided (3)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.076
BayesDel_addAF	Benign	-0.62	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	15
DANN	Uncertain	0.98
DEOGEN2	Benign	0.25	T
Eigen	Benign	-0.55
Eigen_PC	Benign	-0.50
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.80	T
MetaRNN	Benign	0.0024	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.6	L
PhyloP100		2.2
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-0.22	N
REVEL	Benign	0.18
Sift	Benign	0.31	T
Sift4G	Benign	0.33	T
Polyphen		0.0030	B
Vest4		0.028
MPC		0.30
ClinPred		0.0079	T
GERP RS		3.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.060
gMVP		0.44
Mutation Taster		=93/7	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs1805084; hg19: chr18-21112206; COSMIC: COSV52570481; COSMIC: COSV52570481;