rs1805082

Variant names:

• chr18-23540480-T-C
• rs1805082
• NM_000271.5:c.2572A>G

Your query was ambiguous. Multiple possible variants found:

• chr18-23540480-T-C
• chr18-23540480-T-A

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 3P and 20B. PM1 PP2 BP4_Strong BP6_Very_Strong BA1

The NM_000271.5(NPC1):​c.2572A>G​(p.Ile858Val) variant causes a missense change. The variant allele was found at a frequency of 0.487 in 1,607,602 control chromosomes in the GnomAD database, including 193,451 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar.

• Frequency:
  • Genomes: 𝑓 0.47 (16781 hom., cov: 31)
  • Exomes 𝑓: 0.49 (176670 hom.)
• Consequence: NPC1 NM_000271.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:16 O:1
• Conservation: PhyloP100: 4.93
• Publications: 86 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 -17 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 uncertain in NM_000271.5
• 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 C1, Niemann-Pick disease type C, severe early infantile neurologic onset, Niemann-Pick disease type C, late infantile neurologic onset, Niemann-Pick disease type C, adult neurologic onset, Niemann-Pick disease type C, juvenile neurologic onset, Niemann-Pick disease type C, severe perinatal form.
• BP4: Computational evidence support a benign effect (MetaRNN=7.40361E-5).
• BP6: Variant 18-23540480-T-C is Benign according to our data. Variant chr18-23540480-T-C is described in ClinVar as Benign. ClinVar VariationId is 21135.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.612 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.2572A>G	p.Ile858Val	missense	Exon 17 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.2572A>G	p.Ile858Val	missense	Exon 17 of 25	ENSP00000269228.4	O15118-1
	NPC1	ENST00000897526.1		c.2623A>G	p.Ile875Val	missense	Exon 17 of 25	ENSP00000567585.1
	NPC1	ENST00000926494.1		c.2572A>G	p.Ile858Val	missense	Exon 17 of 25	ENSP00000596553.1

Frequencies

GnomAD3 genomes AF: 0.466 AC: 70363 AN: 151124 Hom.: 16762 Cov.: 31

Gnomad AFR AF: 0.380

Gnomad AMI AF: 0.425

Gnomad AMR AF: 0.573

Gnomad ASJ AF: 0.308

Gnomad EAS AF: 0.630

Gnomad SAS AF: 0.492

Gnomad FIN AF: 0.534

Gnomad MID AF: 0.304

Gnomad NFE AF: 0.479

Gnomad OTH AF: 0.444

GnomAD2 exomes AF: 0.499 AC: 125161 AN: 250608 AF XY: 0.493

Gnomad AFR exome AF: 0.378

Gnomad AMR exome AF: 0.654

Gnomad ASJ exome AF: 0.307

Gnomad EAS exome AF: 0.624

Gnomad FIN exome AF: 0.503

Gnomad NFE exome AF: 0.470

Gnomad OTH exome AF: 0.467

GnomAD4 exome AF: 0.489 AC: 711784 AN: 1456382 Hom.: 176670 Cov.: 34 AF XY: 0.487 AC XY: 352658 AN XY: 724846

African (AFR) AF: 0.369 AC: 12301 AN: 33376

American (AMR) AF: 0.645 AC: 28844 AN: 44700

Ashkenazi Jewish (ASJ) AF: 0.303 AC: 7915 AN: 26106

East Asian (EAS) AF: 0.657 AC: 26077 AN: 39672

South Asian (SAS) AF: 0.493 AC: 42500 AN: 86130

European-Finnish (FIN) AF: 0.498 AC: 26433 AN: 53120

Middle Eastern (MID) AF: 0.347 AC: 1997 AN: 5760

European-Non Finnish (NFE) AF: 0.485 AC: 537500 AN: 1107314

Other (OTH) AF: 0.469 AC: 28217 AN: 60204

GnomAD4 genome AF: 0.466 AC: 70442 AN: 151220 Hom.: 16781 Cov.: 31 AF XY: 0.470 AC XY: 34739 AN XY: 73838

African (AFR) AF: 0.380 AC: 15622 AN: 41110

American (AMR) AF: 0.574 AC: 8758 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.308 AC: 1067 AN: 3466

East Asian (EAS) AF: 0.630 AC: 3250 AN: 5160

South Asian (SAS) AF: 0.493 AC: 2358 AN: 4780

European-Finnish (FIN) AF: 0.534 AC: 5496 AN: 10286

Middle Eastern (MID) AF: 0.311 AC: 89 AN: 286

European-Non Finnish (NFE) AF: 0.479 AC: 32480 AN: 67876

Other (OTH) AF: 0.449 AC: 935 AN: 2084

Alfa AF: 0.470 Hom.: 67432

Bravo AF: 0.467

TwinsUK AF: 0.494 AC: 1833

ALSPAC AF: 0.496 AC: 1911

ESP6500AA AF: 0.388 AC: 1711

ESP6500EA AF: 0.471 AC: 4047

ExAC AF: 0.490 AC: 59504

Asia WGS AF: 0.549 AC: 1908 AN: 3478

EpiCase AF: 0.456

EpiControl AF: 0.445

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	7	Niemann-Pick disease, type C1 (8)
-	-	6	not specified (6)
-	-	3	not provided (3)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.059
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.12
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.29	T
Eigen	Benign	-0.054
Eigen_PC	Benign	0.17
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.69	T
MetaRNN	Benign	0.000074	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	1.3	L
PhyloP100		4.9
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-0.72	N
REVEL	Uncertain	0.33
Sift	Benign	0.23	T
Sift4G	Benign	0.28	T
Polyphen		0.047	B
Vest4		0.075
MPC		0.22
ClinPred		0.0081	T
GERP RS		6.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.28
gMVP		0.39
Mutation Taster		=91/9	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.10		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: rs1805082; hg19: chr18-21120444; COSMIC: COSV52582772; COSMIC: COSV52582772;