rs1140458

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_StrongBA1

The NM_000271.5(NPC1):c.2793C>T(p.Asn931Asn) variant causes a splice region, synonymous change. The variant allele was found at a frequency of 0.486 in 1,613,394 control chromosomes in the GnomAD database, including 193,282 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.46 ( 16719 hom., cov: 32)

Exomes 𝑓: 0.49 ( 176563 hom. )

Consequence

NPC1
NM_000271.5 splice_region, synonymous

Scores

Splicing: ADA: 0.9915

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:16O:1

Conservation

PhyloP100: 4.82

Publications

41 publications found

Variant links:

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

NPC1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -16 ACMG points.

BP6

Variant 18-23539813-G-A is Benign according to our data. Variant chr18-23539813-G-A is described in ClinVar as Benign. ClinVar VariationId is 21136.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.608 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.2793C>T	p.Asn931Asn	splice_region synonymous	Exon 18 of 25	NP_000262.2	O15118-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
NPC1	ENST00000269228.10	TSL:1 MANE Select	c.2793C>T	p.Asn931Asn	splice_region synonymous	Exon 18 of 25	ENSP00000269228.4	O15118-1
NPC1	ENST00000897526.1		c.2844C>T	p.Asn948Asn	splice_region synonymous	Exon 18 of 25	ENSP00000567585.1
NPC1	ENST00000926494.1		c.2793C>T	p.Asn931Asn	splice_region synonymous	Exon 18 of 25	ENSP00000596553.1

Frequencies

GnomAD3 genomes

AF:

0.462

AC:

70245

AN:

151888

Hom.:

16700

Cov.:

show subpopulations

Gnomad AFR

AF:

0.376

Gnomad AMI

AF:

0.422

Gnomad AMR

AF:

0.572

Gnomad ASJ

AF:

0.308

Gnomad EAS

AF:

0.626

Gnomad SAS

AF:

0.486

Gnomad FIN

AF:

0.520

Gnomad MID

AF:

0.307

Gnomad NFE

AF:

0.477

Gnomad OTH

AF:

0.439

GnomAD2 exomes

AF:

0.499

AC:

125229

AN:

251178

AF XY:

0.492

show subpopulations

Gnomad AFR exome

AF:

0.378

Gnomad AMR exome

AF:

0.654

Gnomad ASJ exome

AF:

0.307

Gnomad EAS exome

AF:

0.622

Gnomad FIN exome

AF:

0.502

Gnomad NFE exome

AF:

0.470

Gnomad OTH exome

AF:

0.467

GnomAD4 exome

AF:

0.488

AC:

713379

AN:

1461388

Hom.:

176563

Cov.:

AF XY:

0.486

AC XY:

353256

AN XY:

727012

show subpopulations

African (AFR)

AF:

0.368

AC:

12314

AN:

33472

American (AMR)

AF:

0.645

AC:

28837

AN:

44716

Ashkenazi Jewish (ASJ)

AF:

0.303

AC:

7923

AN:

26132

East Asian (EAS)

AF:

0.656

AC:

26041

AN:

39698

South Asian (SAS)

AF:

0.491

AC:

42382

AN:

86246

European-Finnish (FIN)

AF:

0.497

AC:

26519

AN:

53400

Middle Eastern (MID)

AF:

0.348

AC:

1991

AN:

5728

European-Non Finnish (NFE)

AF:

0.485

AC:

539115

AN:

1111636

Other (OTH)

AF:

0.468

AC:

28257

AN:

60360

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.478

Heterozygous variant carriers

19454

38908

58362

77816

97270

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

16028

32056

48084

64112

80140

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.463

AC:

70324

AN:

152006

Hom.:

16719

Cov.:

AF XY:

0.467

AC XY:

34675

AN XY:

74272

show subpopulations

African (AFR)

AF:

0.376

AC:

15600

AN:

41450

American (AMR)

AF:

0.572

AC:

8750

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.308

AC:

1068

AN:

3466

East Asian (EAS)

AF:

0.626

AC:

3237

AN:

5174

South Asian (SAS)

AF:

0.487

AC:

2345

AN:

4820

European-Finnish (FIN)

AF:

0.520

AC:

5477

AN:

10536

Middle Eastern (MID)

AF:

0.310

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.477

AC:

32436

AN:

67962

Other (OTH)

AF:

0.444

AC:

937

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1915

3831

5746

7662

9577

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

648

1296

1944

2592

3240

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.442

Hom.:

9661

Bravo

AF:

0.467

Asia WGS

AF:

0.546

AC:

1899

AN:

3478

EpiCase

AF:

0.455

EpiControl

AF:

0.443

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Niemann-Pick disease, type C1 (8)

not specified (6)

not provided (3)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.28

CADD

Benign

(source)

DANN

Benign

0.86

PhyloP100

4.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Mutation Taster

=6/94

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

0.99

SpliceAI score (max)

0.030

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over