18-23544946-C-CT

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP6_ModerateBS2

The NM_000271.5(NPC1):c.1947+13_1947+14insA variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000511 in 1,329,796 control chromosomes in the GnomAD database, including 4 homozygotes. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.000059 ( 2 hom., cov: 27)

Exomes 𝑓: 0.000050 ( 2 hom. )

Consequence

NPC1
NM_000271.5 intron

Scores

Not classified

Clinical Significance

Likely benign criteria provided, single submitter B:2

Conservation

PhyloP100: -0.996

Publications

0 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: Likely_benign. The variant received -6 ACMG points.

BP6

Variant 18-23544946-C-CT is Benign according to our data. Variant chr18-23544946-C-CT is described in ClinVar as Likely_benign. ClinVar VariationId is 1539541.Status of the report is criteria_provided_single_submitter, 1 stars.

BS2

High Homozygotes in GnomAd4 at 2 AR gene

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.1947+13_1947+14insA		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.1947+13_1947+14insA	intron	N/A	ENSP00000269228.4	O15118-1
NPC1	ENST00000897526.1		c.1998+13_1998+14insA	intron	N/A	ENSP00000567585.1
NPC1	ENST00000926494.1		c.1947+13_1947+14insA	intron	N/A	ENSP00000596553.1

Frequencies

GnomAD3 genomes

AF:

0.0000589

AC:

AN:

135902

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000724

Gnomad ASJ

AF:

0.000303

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000244

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000657

Gnomad OTH

AF:

0.000534

GnomAD4 exome

AF:

0.0000503

AC:

AN:

1193800

Hom.:

Cov.:

AF XY:

0.0000564

AC XY:

AN XY:

602958

show subpopulations

African (AFR)

AF:

0.0000330

AC:

AN:

30282

American (AMR)

AF:

0.000192

AC:

AN:

41612

Ashkenazi Jewish (ASJ)

AF:

0.000488

AC:

AN:

24582

East Asian (EAS)

AF:

0.00

AC:

AN:

32172

South Asian (SAS)

AF:

0.00

AC:

AN:

79238

European-Finnish (FIN)

AF:

0.00

AC:

AN:

47572

Middle Eastern (MID)

AF:

0.000190

AC:

AN:

5262

European-Non Finnish (NFE)

AF:

0.0000397

AC:

AN:

882396

Other (OTH)

AF:

0.0000592

AC:

AN:

50684

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.552

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<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:

0.0000588

AC:

AN:

135996

Hom.:

Cov.:

AF XY:

0.0000751

AC XY:

AN XY:

66576

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

36722

American (AMR)

AF:

0.0000723

AC:

AN:

13826

Ashkenazi Jewish (ASJ)

AF:

0.000303

AC:

AN:

3304

East Asian (EAS)

AF:

0.00

AC:

AN:

4392

South Asian (SAS)

AF:

0.000245

AC:

AN:

4088

European-Finnish (FIN)

AF:

0.00

AC:

AN:

9770

Middle Eastern (MID)

AF:

0.00

AC:

AN:

280

European-Non Finnish (NFE)

AF:

0.0000657

AC:

AN:

60900

Other (OTH)

AF:

0.000529

AC:

AN:

1892

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.663

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<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:

0.00

Hom.:

ClinVar

ClinVar submissions

Significance:Likely benign

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

Niemann-Pick disease, type C1 (1)

NPC1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

-1.0

Mutation Taster

=100/0

polymorphism

(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

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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