rs144415945

Variant names:

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_StrongBP6BP7BS1

The NM_000271.5(NPC1):c.66A>G(p.Ser22Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00105 in 1,614,158 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0010 ( 1 hom., cov: 33)

Exomes 𝑓: 0.0011 ( 1 hom. )

Consequence

NPC1
NM_000271.5 synonymous

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:10

Conservation

PhyloP100: 0.131

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: Benign. The variant received -10 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.57).

BP6

Variant 18-23573566-T-C is Benign according to our data. Variant chr18-23573566-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 255701.

BP7

Synonymous conserved (PhyloP=0.131 with no splicing effect.

BS1

Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00102 (155/152324) while in subpopulation AMR AF = 0.00288 (44/15296). AF 95% confidence interval is 0.0022. There are 1 homozygotes in GnomAd4. There are 76 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

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.66A>G	p.Ser22Ser	synonymous	Exon 2 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.66A>G	p.Ser22Ser	synonymous	Exon 2 of 25	ENSP00000269228.4	O15118-1
NPC1	ENST00000897526.1		c.66A>G	p.Ser22Ser	synonymous	Exon 2 of 25	ENSP00000567585.1
NPC1	ENST00000926494.1		c.66A>G	p.Ser22Ser	synonymous	Exon 2 of 25	ENSP00000596553.1

Frequencies

GnomAD3 genomes

AF:

0.00102

AC:

155

AN:

152206

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000362

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00288

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00129

Gnomad OTH

AF:

0.00335

GnomAD2 exomes

AF:

0.00109

AC:

273

AN:

251426

AF XY:

0.00107

show subpopulations

Gnomad AFR exome

AF:

0.000369

Gnomad AMR exome

AF:

0.00225

Gnomad ASJ exome

AF:

0.000397

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000462

Gnomad NFE exome

AF:

0.00151

Gnomad OTH exome

AF:

0.00163

GnomAD4 exome

AF:

0.00105

AC:

1541

AN:

1461834

Hom.:

Cov.:

AF XY:

0.00107

AC XY:

775

AN XY:

727218

show subpopulations

African (AFR)

AF:

0.000239

AC:

AN:

33478

American (AMR)

AF:

0.00235

AC:

105

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.000536

AC:

AN:

26132

East Asian (EAS)

AF:

0.00

AC:

AN:

39684

South Asian (SAS)

AF:

0.0000232

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.000131

AC:

AN:

53418

Middle Eastern (MID)

AF:

0.000693

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00119

AC:

1326

AN:

1111980

Other (OTH)

AF:

0.00124

AC:

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.474

Heterozygous variant carriers

168

253

337

421

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

132

176

220

<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:

0.00102

AC:

155

AN:

152324

Hom.:

Cov.:

AF XY:

0.00102

AC XY:

AN XY:

74488

show subpopulations

African (AFR)

AF:

0.000361

AC:

AN:

41576

American (AMR)

AF:

0.00288

AC:

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5190

South Asian (SAS)

AF:

0.00

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10612

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00129

AC:

AN:

68036

Other (OTH)

AF:

0.00332

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

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:

0.00120

Hom.:

Bravo

AF:

0.00107

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00136

EpiControl

AF:

0.00124

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (6)

Niemann-Pick disease, type C1 (2)

not specified (2)

Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.57

CADD

Benign

8.3

(source)

DANN

Benign

0.66

PhyloP100

0.13

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.6

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

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