chr18-23560468-T-C

Variant names:

• chr18-23560468-T-C
• rs1805081
• NM_000271.5:c.644A>G

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.644A>G​(p.His215Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.379 in 1,613,400 control chromosomes in the GnomAD database, including 123,029 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. H215H) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.29 (8271 hom., cov: 32)
  • Exomes 𝑓: 0.39 (114758 hom.)
• Consequence: NPC1 NM_000271.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:15
• Conservation: PhyloP100: 0.593
• Publications: 176 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 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=0.0017139614).
• BP6: Variant 18-23560468-T-C is Benign according to our data. Variant chr18-23560468-T-C is described in ClinVar as Benign. ClinVar VariationId is 92714.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.407 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.644A>G	p.His215Arg	missense	Exon 6 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.644A>G	p.His215Arg	missense	Exon 6 of 25	ENSP00000269228.4	O15118-1
	NPC1	ENST00000897526.1		c.644A>G	p.His215Arg	missense	Exon 6 of 25	ENSP00000567585.1
	NPC1	ENST00000926494.1		c.644A>G	p.His215Arg	missense	Exon 6 of 25	ENSP00000596553.1

Frequencies

GnomAD3 genomes AF: 0.294 AC: 44703 AN: 152014 Hom.: 8271 Cov.: 32

Gnomad AFR AF: 0.0792

Gnomad AMI AF: 0.322

Gnomad AMR AF: 0.269

Gnomad ASJ AF: 0.257

Gnomad EAS AF: 0.250

Gnomad SAS AF: 0.257

Gnomad FIN AF: 0.478

Gnomad MID AF: 0.197

Gnomad NFE AF: 0.411

Gnomad OTH AF: 0.267

GnomAD2 exomes AF: 0.331 AC: 82692 AN: 250070 AF XY: 0.336

Gnomad AFR exome AF: 0.0702

Gnomad AMR exome AF: 0.247

Gnomad ASJ exome AF: 0.260

Gnomad EAS exome AF: 0.246

Gnomad FIN exome AF: 0.457

Gnomad NFE exome AF: 0.404

Gnomad OTH exome AF: 0.330

GnomAD4 exome AF: 0.388 AC: 566798 AN: 1461268 Hom.: 114758 Cov.: 40 AF XY: 0.385 AC XY: 279556 AN XY: 726982

African (AFR) AF: 0.0597 AC: 2000 AN: 33476

American (AMR) AF: 0.253 AC: 11327 AN: 44702

Ashkenazi Jewish (ASJ) AF: 0.258 AC: 6738 AN: 26134

East Asian (EAS) AF: 0.267 AC: 10608 AN: 39694

South Asian (SAS) AF: 0.280 AC: 24127 AN: 86216

European-Finnish (FIN) AF: 0.454 AC: 24225 AN: 53380

Middle Eastern (MID) AF: 0.208 AC: 1188 AN: 5722

European-Non Finnish (NFE) AF: 0.419 AC: 465533 AN: 1111560

Other (OTH) AF: 0.349 AC: 21052 AN: 60384

GnomAD4 genome AF: 0.294 AC: 44713 AN: 152132 Hom.: 8271 Cov.: 32 AF XY: 0.293 AC XY: 21757 AN XY: 74360

African (AFR) AF: 0.0790 AC: 3281 AN: 41540

American (AMR) AF: 0.269 AC: 4109 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.257 AC: 894 AN: 3472

East Asian (EAS) AF: 0.250 AC: 1297 AN: 5180

South Asian (SAS) AF: 0.258 AC: 1246 AN: 4824

European-Finnish (FIN) AF: 0.478 AC: 5049 AN: 10554

Middle Eastern (MID) AF: 0.202 AC: 59 AN: 292

European-Non Finnish (NFE) AF: 0.411 AC: 27914 AN: 67972

Other (OTH) AF: 0.271 AC: 572 AN: 2112

Alfa AF: 0.359 Hom.: 34038

Bravo AF: 0.269

TwinsUK AF: 0.420 AC: 1557

ALSPAC AF: 0.427 AC: 1645

ESP6500AA AF: 0.0878 AC: 387

ESP6500EA AF: 0.403 AC: 3462

ExAC AF: 0.327 AC: 39711

Asia WGS AF: 0.231 AC: 804 AN: 3478

EpiCase AF: 0.387

EpiControl AF: 0.371

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	7	Niemann-Pick disease, type C1 (7)
-	-	6	not specified (6)
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.052
BayesDel_addAF	Benign	-0.58	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	5.3
DANN	Benign	0.45
DEOGEN2	Uncertain	0.48	T
Eigen	Benign	-0.96
Eigen_PC	Benign	-0.93
FATHMM_MKL	Benign	0.28	N
LIST_S2	Benign	0.59	T
MetaRNN	Benign	0.0017	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.2	L
PhyloP100		0.59
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-1.4	N
REVEL	Benign	0.15
Sift	Benign	0.53	T
Sift4G	Benign	0.58	T
Polyphen		0.0	B
Vest4		0.026
MPC		0.31
ClinPred		0.0039	T
GERP RS		-1.1
PromoterAI		0.028	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.11
gMVP		0.29
Mutation Taster		=98/2	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1805081; hg19: chr18-21140432; COSMIC: COSV52576882; COSMIC: COSV52576882;