18-23544981-C-G

Variant names:

• chr18-23544981-C-G
• rs1788799
• NM_000271.5:c.1926G>C

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.1926G>C​(p.Met642Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.687 in 1,530,962 control chromosomes in the GnomAD database, including 374,159 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 nucleotide change resulting in the same amino acid substitution has been previously reported as Benign in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M642T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.74 (40038 hom., cov: 22)
  • Exomes 𝑓: 0.68 (334121 hom.)
• Consequence: NPC1 NM_000271.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:17
• Conservation: PhyloP100: 2.90
• Publications: 73 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 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 4 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 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=1.0263868E-6).
• BP6: Variant 18-23544981-C-G is Benign according to our data. Variant chr18-23544981-C-G is described in ClinVar as Benign. ClinVar VariationId is 92701.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.901 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.1926G>C	p.Met642Ile	missense	Exon 12 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.1926G>C	p.Met642Ile	missense	Exon 12 of 25	ENSP00000269228.4	O15118-1
	NPC1	ENST00000897526.1		c.1977G>C	p.Met659Ile	missense	Exon 12 of 25	ENSP00000567585.1
	NPC1	ENST00000926494.1		c.1926G>C	p.Met642Ile	missense	Exon 12 of 25	ENSP00000596553.1

Frequencies

GnomAD3 genomes AF: 0.740 AC: 104617 AN: 141462 Hom.: 39989 Cov.: 22

Gnomad AFR AF: 0.909

Gnomad AMI AF: 0.719

Gnomad AMR AF: 0.744

Gnomad ASJ AF: 0.579

Gnomad EAS AF: 0.923

Gnomad SAS AF: 0.761

Gnomad FIN AF: 0.604

Gnomad MID AF: 0.644

Gnomad NFE AF: 0.650

Gnomad OTH AF: 0.698

GnomAD2 exomes AF: 0.729 AC: 174136 AN: 238838 AF XY: 0.720

Gnomad AFR exome AF: 0.924

Gnomad AMR exome AF: 0.828

Gnomad ASJ exome AF: 0.578

Gnomad EAS exome AF: 0.935

Gnomad FIN exome AF: 0.659

Gnomad NFE exome AF: 0.653

Gnomad OTH exome AF: 0.693

GnomAD4 exome AF: 0.682 AC: 947164 AN: 1389384 Hom.: 334121 Cov.: 33 AF XY: 0.682 AC XY: 470282 AN XY: 689718

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.921 AC: 30440 AN: 33068

American (AMR) AF: 0.821 AC: 34961 AN: 42608

Ashkenazi Jewish (ASJ) AF: 0.575 AC: 14163 AN: 24622

East Asian (EAS) AF: 0.944 AC: 36721 AN: 38914

South Asian (SAS) AF: 0.768 AC: 62468 AN: 81360

European-Finnish (FIN) AF: 0.660 AC: 33153 AN: 50202

Middle Eastern (MID) AF: 0.631 AC: 3514 AN: 5570

European-Non Finnish (NFE) AF: 0.655 AC: 691882 AN: 1055624

Other (OTH) AF: 0.694 AC: 39862 AN: 57416

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.740 AC: 104728 AN: 141578 Hom.: 40038 Cov.: 22 AF XY: 0.739 AC XY: 50240 AN XY: 67968

African (AFR) AF: 0.909 AC: 35552 AN: 39118

American (AMR) AF: 0.744 AC: 9866 AN: 13256

Ashkenazi Jewish (ASJ) AF: 0.579 AC: 1960 AN: 3386

East Asian (EAS) AF: 0.922 AC: 4390 AN: 4762

South Asian (SAS) AF: 0.760 AC: 3325 AN: 4374

European-Finnish (FIN) AF: 0.604 AC: 4897 AN: 8104

Middle Eastern (MID) AF: 0.633 AC: 171 AN: 270

European-Non Finnish (NFE) AF: 0.650 AC: 42571 AN: 65482

Other (OTH) AF: 0.701 AC: 1369 AN: 1954

Alfa AF: 0.659 Hom.: 22488

Bravo AF: 0.763

TwinsUK AF: 0.655 AC: 2427

ALSPAC AF: 0.645 AC: 2484

ESP6500AA AF: 0.910 AC: 4008

ESP6500EA AF: 0.645 AC: 5547

ExAC AF: 0.718 AC: 87148

Asia WGS AF: 0.844 AC: 2934 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	8	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	0.079
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.31
CADD	Benign	16
DANN	Benign	0.77
DEOGEN2	Benign	0.24	T
Eigen	Benign	-0.69
Eigen_PC	Benign	-0.36
FATHMM_MKL	Benign	0.22	N
LIST_S2	Benign	0.29	T
MetaRNN	Benign	0.0000010	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	-2.1	N
PhyloP100		2.9
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	1.6	N
REVEL	Benign	0.26
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.10
MutPred		0.24		Gain of MoRF binding (P = 0.1764)
MPC		0.28
ClinPred		0.0077	T
GERP RS		5.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.15
gMVP		0.19
Mutation Taster		=84/16	polymorphism

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: rs1788799; hg19: chr18-21124945; COSMIC: COSV99342159; COSMIC: COSV99342159;