18-23531886-CCTTTACA-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP6BS1BS2

The NM_000271.5(NPC1):c.*309_*315delTGTAAAG variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00787 in 1,443,394 control chromosomes in the GnomAD database, including 74 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0064 ( 9 hom., cov: 32)

Exomes 𝑓: 0.0080 ( 65 hom. )

Consequence

NPC1
NM_000271.5 3_prime_UTR

Scores

Not classified

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:1

Conservation

PhyloP100: 2.86

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 links:

RMC1 (HGNC:24326): (regulator of MON1-CCZ1) This gene encodes a colon cancer associated protein. [provided by RefSeq, Jan 2013]

RMC1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -9 ACMG points.

BP6

Variant 18-23531886-CCTTTACA-C is Benign according to our data. Variant chr18-23531886-CCTTTACA-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 326243.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Likely_benign=1}.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00641 (970/151368) while in subpopulation NFE AF = 0.0091 (618/67926). AF 95% confidence interval is 0.0085. There are 9 homozygotes in GnomAd4. There are 496 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 9 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NPC1	NM_000271.5 link	c.309_315delTGTAAAG		3_prime_UTR_variant	Exon 25 of 25	ENST00000269228.10	NP_000262.2
RMC1	NM_013326.5 link	c.183_189delCTTTACA		downstream_gene_variant		ENST00000269221.8	NP_037458.3

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
NPC1	ENST00000269228.10 link	c.309_315delTGTAAAG	3_prime_UTR_variant	Exon 25 of 25	1	NM_000271.5	ENSP00000269228.4	O15118-1
RMC1	ENST00000269221.8 link	c.183_189delCTTTACA	downstream_gene_variant		1	NM_013326.5	ENSP00000269221.2	Q96DM3
RMC1	ENST00000590868.5 link	c.183_189delCTTTACA	downstream_gene_variant		2		ENSP00000467007.1	K7ENL9
RMC1	ENST00000615148.5 link	c.203_209delCTTTACA	downstream_gene_variant		5		ENSP00000482573.2	A0A087WZD4
RMC1	ENST00000589215.5 link	n.1690_1696delCTTTACA	downstream_gene_variant		2		ENSP00000467852.1	K7EQJ3

Frequencies

GnomAD3 genomes

AF:

0.00641

AC:

970

AN:

151252

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00114

Gnomad AMI

AF:

0.00659

Gnomad AMR

AF:

0.00238

Gnomad ASJ

AF:

0.00115

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00385

Gnomad FIN

AF:

0.0221

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00911

Gnomad OTH

AF:

0.00434

GnomAD4 exome

AF:

0.00804

AC:

10391

AN:

1292026

Hom.:

AF XY:

0.00789

AC XY:

4960

AN XY:

628432

show subpopulations

African (AFR)

AF:

0.000846

AC:

AN:

28358

American (AMR)

AF:

0.00201

AC:

AN:

20370

Ashkenazi Jewish (ASJ)

AF:

0.000315

AC:

AN:

19074

East Asian (EAS)

AF:

0.0000285

AC:

AN:

35050

South Asian (SAS)

AF:

0.00452

AC:

283

AN:

62582

European-Finnish (FIN)

AF:

0.0187

AC:

583

AN:

31132

Middle Eastern (MID)

AF:

0.00138

AC:

AN:

3626

European-Non Finnish (NFE)

AF:

0.00882

AC:

9153

AN:

1038102

Other (OTH)

AF:

0.00549

AC:

295

AN:

53732

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.455

Heterozygous variant carriers

554

1108

1663

2217

2771

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00641

AC:

970

AN:

151368

Hom.:

Cov.:

AF XY:

0.00671

AC XY:

496

AN XY:

73876

show subpopulations

African (AFR)

AF:

0.00114

AC:

AN:

41202

American (AMR)

AF:

0.00237

AC:

AN:

15176

Ashkenazi Jewish (ASJ)

AF:

0.00115

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5160

South Asian (SAS)

AF:

0.00407

AC:

AN:

4668

European-Finnish (FIN)

AF:

0.0221

AC:

231

AN:

10466

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00910

AC:

618

AN:

67926

Other (OTH)

AF:

0.00429

AC:

AN:

2096

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.491

Heterozygous variant carriers

136

182

227

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00923

Hom.:

Bravo

AF:

0.00455

Asia WGS

AF:

0.000577

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:1

Jul 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

NPC1: BS2 -

Breakthrough Genomics, Breakthrough Genomics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Niemann-Pick disease, type C

Uncertain:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

2.9

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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18-23531886-CCTTTACA-C

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