rs6507720

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000271.5(NPC1):c.2911+28T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.505 in 1,523,196 control chromosomes in the GnomAD database, including 198,353 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.56 ( 24469 hom., cov: 33)

Exomes 𝑓: 0.50 ( 173884 hom. )

Consequence

NPC1
NM_000271.5 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: -0.445

Publications

28 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 -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.86).

BP6

Variant 18-23539327-A-G is Benign according to our data. Variant chr18-23539327-A-G is described in ClinVar as Benign. ClinVar VariationId is 255695.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.696 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.2911+28T>C		intron	N/A	NP_000262.2	O15118-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
NPC1	ENST00000269228.10	TSL:1 MANE Select	c.2911+28T>C	intron	N/A	ENSP00000269228.4	O15118-1
NPC1	ENST00000897526.1		c.2962+28T>C	intron	N/A	ENSP00000567585.1
NPC1	ENST00000926494.1		c.2911+28T>C	intron	N/A	ENSP00000596553.1

Frequencies

GnomAD3 genomes

AF:

0.556

AC:

84552

AN:

152008

Hom.:

24425

Cov.:

show subpopulations

Gnomad AFR

AF:

0.703

Gnomad AMI

AF:

0.424

Gnomad AMR

AF:

0.603

Gnomad ASJ

AF:

0.308

Gnomad EAS

AF:

0.626

Gnomad SAS

AF:

0.499

Gnomad FIN

AF:

0.519

Gnomad MID

AF:

0.329

Gnomad NFE

AF:

0.479

Gnomad OTH

AF:

0.493

GnomAD2 exomes

AF:

0.525

AC:

129031

AN:

245706

AF XY:

0.512

show subpopulations

Gnomad AFR exome

AF:

0.713

Gnomad AMR exome

AF:

0.671

Gnomad ASJ exome

AF:

0.307

Gnomad EAS exome

AF:

0.623

Gnomad FIN exome

AF:

0.503

Gnomad NFE exome

AF:

0.471

Gnomad OTH exome

AF:

0.477

GnomAD4 exome

AF:

0.499

AC:

684094

AN:

1371070

Hom.:

173884

Cov.:

AF XY:

0.495

AC XY:

340004

AN XY:

686280

show subpopulations

African (AFR)

AF:

0.703

AC:

22339

AN:

31762

American (AMR)

AF:

0.663

AC:

29325

AN:

44212

Ashkenazi Jewish (ASJ)

AF:

0.303

AC:

7698

AN:

25424

East Asian (EAS)

AF:

0.657

AC:

25787

AN:

39234

South Asian (SAS)

AF:

0.502

AC:

42115

AN:

83956

European-Finnish (FIN)

AF:

0.497

AC:

26431

AN:

53162

Middle Eastern (MID)

AF:

0.359

AC:

2008

AN:

5592

European-Non Finnish (NFE)

AF:

0.486

AC:

500286

AN:

1030272

Other (OTH)

AF:

0.489

AC:

28105

AN:

57456

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

16836

33672

50509

67345

84181

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

14560

29120

43680

58240

72800

<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:

0.557

AC:

84661

AN:

152126

Hom.:

24469

Cov.:

AF XY:

0.557

AC XY:

41421

AN XY:

74364

show subpopulations

African (AFR)

AF:

0.703

AC:

29180

AN:

41504

American (AMR)

AF:

0.603

AC:

9214

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.308

AC:

1068

AN:

3472

East Asian (EAS)

AF:

0.626

AC:

3231

AN:

5164

South Asian (SAS)

AF:

0.500

AC:

2409

AN:

4818

European-Finnish (FIN)

AF:

0.519

AC:

5487

AN:

10580

Middle Eastern (MID)

AF:

0.330

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.479

AC:

32532

AN:

67986

Other (OTH)

AF:

0.500

AC:

1056

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1898

3795

5693

7590

9488

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

718

1436

2154

2872

3590

<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:

0.485

Hom.:

24582

Bravo

AF:

0.572

Asia WGS

AF:

0.571

AC:

1984

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

Niemann-Pick disease, type C1 (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.86

CADD

Benign

1.1

(source)

DANN

Benign

0.39

PhyloP100

-0.45

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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