NM_000271.5:c.1947+10G>C

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_000271.5(NPC1):c.1947+10G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0088 in 1,415,958 control chromosomes in the GnomAD database, including 670 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0070 ( 107 hom., cov: 27)

Exomes 𝑓: 0.0090 ( 563 hom. )

Consequence

NPC1
NM_000271.5 intron

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:13

Conservation

PhyloP100: 0.104

Publications

2 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, Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), G2P, Genomics England PanelApp, Myriad Women’s Health
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=-0.84).

BP6

Variant 18-23544950-C-G is Benign according to our data. Variant chr18-23544950-C-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 92702.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00704 (1012/143798) while in subpopulation NFE AF = 0.0104 (660/63298). AF 95% confidence interval is 0.00977. There are 107 homozygotes in GnomAd4. There are 521 alleles in the male GnomAd4 subpopulation. Median coverage is 27. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 107 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NPC1	NM_000271.5 link	c.1947+10G>C		intron_variant	Intron 12 of 24	ENST00000269228.10	NP_000262.2

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
NPC1	ENST00000269228.10 link	c.1947+10G>C	intron_variant	Intron 12 of 24	1	NM_000271.5	ENSP00000269228.4	O15118-1
NPC1	ENST00000591051.1 link	c.1023+10G>C	intron_variant	Intron 5 of 17	2		ENSP00000467636.1	K7EQ23
NPC1	ENST00000540608.5 link	n.1861+10G>C	intron_variant	Intron 10 of 15	2

Frequencies

GnomAD3 genomes

AF:

0.00704

AC:

1011

AN:

143684

Hom.:

107

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00127

Gnomad AMI

AF:

0.00708

Gnomad AMR

AF:

0.00270

Gnomad ASJ

AF:

0.00149

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00394

Gnomad FIN

AF:

0.0226

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0104

Gnomad OTH

AF:

0.00358

GnomAD2 exomes

AF:

0.00788

AC:

1923

AN:

244166

AF XY:

0.00797

show subpopulations

Gnomad AFR exome

AF:

0.00123

Gnomad AMR exome

AF:

0.00176

Gnomad ASJ exome

AF:

0.000200

Gnomad EAS exome

AF:

0.0000550

Gnomad FIN exome

AF:

0.0257

Gnomad NFE exome

AF:

0.0103

Gnomad OTH exome

AF:

0.00690

GnomAD4 exome

AF:

0.00900

AC:

11455

AN:

1272160

Hom.:

563

Cov.:

AF XY:

0.00886

AC XY:

5669

AN XY:

640090

show subpopulations

African (AFR)

AF:

0.00102

AC:

AN:

31238

American (AMR)

AF:

0.00170

AC:

AN:

42970

Ashkenazi Jewish (ASJ)

AF:

0.000359

AC:

AN:

25068

East Asian (EAS)

AF:

0.0000289

AC:

AN:

34646

South Asian (SAS)

AF:

0.00476

AC:

390

AN:

81850

European-Finnish (FIN)

AF:

0.0238

AC:

1167

AN:

49066

Middle Eastern (MID)

AF:

0.000916

AC:

AN:

5458

European-Non Finnish (NFE)

AF:

0.00995

AC:

9434

AN:

948374

Other (OTH)

AF:

0.00643

AC:

344

AN:

53490

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.602

Heterozygous variant carriers

307

613

920

1226

1533

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

306

612

918

1224

1530

<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:

0.00704

AC:

1012

AN:

143798

Hom.:

107

Cov.:

AF XY:

0.00740

AC XY:

521

AN XY:

70358

show subpopulations

African (AFR)

AF:

0.00126

AC:

AN:

40346

American (AMR)

AF:

0.00270

AC:

AN:

14458

Ashkenazi Jewish (ASJ)

AF:

0.00149

AC:

AN:

3364

East Asian (EAS)

AF:

0.00

AC:

AN:

4908

South Asian (SAS)

AF:

0.00418

AC:

AN:

4310

European-Finnish (FIN)

AF:

0.0226

AC:

226

AN:

10004

Middle Eastern (MID)

AF:

0.00

AC:

AN:

290

European-Non Finnish (NFE)

AF:

0.0104

AC:

660

AN:

63298

Other (OTH)

AF:

0.00355

AC:

AN:

1972

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.604

Heterozygous variant carriers

126

158

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.00454

Hom.:

Bravo

AF:

0.00467

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:13

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Niemann-Pick disease, type C1

Benign:6

Oct 21, 2019

Natera, Inc.

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jan 30, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 17, 2022

Fulgent Genetics, Fulgent Genetics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Jun 20, 2016

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not provided

Benign:4

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Mar 03, 2015

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 10, 2017

Mayo Clinic Laboratories, Mayo Clinic

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

May 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

NPC1: BS2 -

not specified

Benign:3

Feb 22, 2013

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.84

CADD

Benign

0.53

(source)

DANN

Benign

0.30

PhyloP100

0.10

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over