chr18-23544943-A-AC

Variant names:

Variant summary

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

The NM_000271.5(NPC1):c.1947+16dupG variant causes a intron change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.22 ( 5470 hom., cov: 0)

Exomes 𝑓: 0.17 ( 6285 hom. )

Consequence

NPC1
NM_000271.5 intron

Scores

Not classified

Clinical Significance

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

Conservation

PhyloP100: -0.952

Publications

3 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 -16 ACMG points.

BP6

Variant 18-23544943-A-AC is Benign according to our data. Variant chr18-23544943-A-AC is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 193982.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.245 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NPC1	NM_000271.5 link	c.1947+16dupG		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+16_1947+17insG	intron_variant	Intron 12 of 24	1	NM_000271.5	ENSP00000269228.4	O15118-1
NPC1	ENST00000591051.1 link	c.1023+16_1023+17insG	intron_variant	Intron 5 of 17	2		ENSP00000467636.1	K7EQ23
NPC1	ENST00000540608.5 link	n.1861+16_1861+17insG	intron_variant	Intron 10 of 15	2

Frequencies

GnomAD3 genomes

AF:

0.219

AC:

22879

AN:

104660

Hom.:

5476

Cov.:

show subpopulations

Gnomad AFR

AF:

0.175

Gnomad AMI

AF:

0.403

Gnomad AMR

AF:

0.225

Gnomad ASJ

AF:

0.317

Gnomad EAS

AF:

0.0226

Gnomad SAS

AF:

0.248

Gnomad FIN

AF:

0.221

Gnomad MID

AF:

0.360

Gnomad NFE

AF:

0.249

Gnomad OTH

AF:

0.241

GnomAD4 exome

AF:

0.173

AC:

159477

AN:

921926

Hom.:

6285

Cov.:

AF XY:

0.175

AC XY:

82374

AN XY:

471122

show subpopulations

African (AFR)

AF:

0.166

AC:

4221

AN:

25368

American (AMR)

AF:

0.126

AC:

4538

AN:

35958

Ashkenazi Jewish (ASJ)

AF:

0.234

AC:

4855

AN:

20740

East Asian (EAS)

AF:

0.0437

AC:

1156

AN:

26458

South Asian (SAS)

AF:

0.186

AC:

13193

AN:

70786

European-Finnish (FIN)

AF:

0.170

AC:

6749

AN:

39690

Middle Eastern (MID)

AF:

0.223

AC:

939

AN:

4220

European-Non Finnish (NFE)

AF:

0.177

AC:

116648

AN:

658464

Other (OTH)

AF:

0.178

AC:

7178

AN:

40242

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

Heterozygous variant carriers

3928

7857

11785

15714

19642

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

3706

7412

11118

14824

18530

<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:

0.218

AC:

22872

AN:

104708

Hom.:

5470

Cov.:

AF XY:

0.218

AC XY:

10823

AN XY:

49606

show subpopulations

African (AFR)

AF:

0.175

AC:

5502

AN:

31402

American (AMR)

AF:

0.225

AC:

2012

AN:

8946

Ashkenazi Jewish (ASJ)

AF:

0.317

AC:

887

AN:

2802

East Asian (EAS)

AF:

0.0227

AC:

AN:

3614

South Asian (SAS)

AF:

0.247

AC:

749

AN:

3030

European-Finnish (FIN)

AF:

0.221

AC:

1095

AN:

4952

Middle Eastern (MID)

AF:

0.343

AC:

AN:

216

European-Non Finnish (NFE)

AF:

0.249

AC:

11865

AN:

47658

Other (OTH)

AF:

0.240

AC:

348

AN:

1448

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.530

Heterozygous variant carriers

437

875

1312

1750

2187

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

206

412

618

824

1030

<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:

0.142

Hom.:

365

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

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

May 09, 2016

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Sep 21, 2015

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Nov 08, 2016

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:5

Jan 25, 2018

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: The NPC1 c.1947+16dupG variant involves the alteration of a non-conserved intronic nucleotide. One in silico tool predicts a benign outcome for this variant. 5/5 splice prediction tools predict no significant impact on normal splicing. This variant was found in 803/5008 control chromosomes at a frequency of 0.1603435 (in the 1000 Genomes Project), which is approximately 60 times the estimated maximal expected allele frequency of a pathogenic NPC1 variant (0.0027735), suggesting this variant is likely a benign polymorphism. In addition, multiple clinical diagnostic laboratories classified this variant as benign. The variant of interest has not, to our knowledge, been reported in affected individuals via publications nor evaluated for functional impact by in vivo/vitro studies. Taken together, this variant is classified as benign. -

Dec 01, 2014

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus 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

- -

Apr 21, 2015

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

not provided

Benign:1

Clinical Genetics, Academic Medical Center

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

NPC1-related disorder

Benign:1

Oct 11, 2023

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

-0.95

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