18-23544943-ACCCC-ACCCCCC

Variant names:

• chr18-23544943-A-ACC
• rs3837910
• NM_000271.5:c.1947+15_1947+16dupGG

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_Moderate BS1 BS2

The NM_000271.5(NPC1):​c.1947+15_1947+16dupGG variant causes a intron change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.022 (341 hom., cov: 0)
  • Exomes 𝑓: 0.047 (1638 hom.)
• Consequence: NPC1 NM_000271.5 intron
• Clinical Significance: Benign criteria provided, single submitter B:7
• Conservation: PhyloP100: -0.952
• Publications: 3 publications found

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

ACMG classification

Our verdict: Benign. The variant received -10 ACMG points.

• BP6: Variant 18-23544943-A-ACC is Benign according to our data. Variant chr18-23544943-A-ACC is described in ClinVar as Benign. ClinVar VariationId is 518276.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0221 (2318/104682) while in subpopulation AFR AF = 0.0264 (828/31408). AF 95% confidence interval is 0.0249. There are 341 homozygotes in GnomAd4. There are 1123 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 341 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NPC1	NM_000271.5	c.1947+15_1947+16dupGG		intron_variant	Intron 12 of 24	ENST00000269228.10	NP_000262.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NPC1	ENST00000269228.10	c.1947+16_1947+17insGG		intron_variant	Intron 12 of 24	1	NM_000271.5	ENSP00000269228.4
NPC1	ENST00000591051.1	c.1023+16_1023+17insGG		intron_variant	Intron 5 of 17	2		ENSP00000467636.1
NPC1	ENST00000540608.5	n.1861+16_1861+17insGG		intron_variant	Intron 10 of 15	2

Frequencies

GnomAD3 genomes AF: 0.0222 AC: 2320 AN: 104638 Hom.: 342 Cov.: 0

Gnomad AFR AF: 0.0264

Gnomad AMI AF: 0.00313

Gnomad AMR AF: 0.0194

Gnomad ASJ AF: 0.0382

Gnomad EAS AF: 0.00883

Gnomad SAS AF: 0.0233

Gnomad FIN AF: 0.0115

Gnomad MID AF: 0.0212

Gnomad NFE AF: 0.0214

Gnomad OTH AF: 0.0174

GnomAD4 exome AF: 0.0465 AC: 41714 AN: 896124 Hom.: 1638 Cov.: 19 AF XY: 0.0481 AC XY: 21978 AN XY: 457298

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.108 AC: 2511 AN: 23316

American (AMR) AF: 0.138 AC: 4674 AN: 33986

Ashkenazi Jewish (ASJ) AF: 0.0365 AC: 740 AN: 20248

East Asian (EAS) AF: 0.123 AC: 2947 AN: 24032

South Asian (SAS) AF: 0.0706 AC: 4785 AN: 67734

European-Finnish (FIN) AF: 0.0460 AC: 1791 AN: 38908

Middle Eastern (MID) AF: 0.0337 AC: 137 AN: 4064

European-Non Finnish (NFE) AF: 0.0346 AC: 22290 AN: 644840

Other (OTH) AF: 0.0472 AC: 1839 AN: 38996

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0221 AC: 2318 AN: 104682 Hom.: 341 Cov.: 0 AF XY: 0.0226 AC XY: 1123 AN XY: 49586

African (AFR) AF: 0.0264 AC: 828 AN: 31408

American (AMR) AF: 0.0194 AC: 173 AN: 8930

Ashkenazi Jewish (ASJ) AF: 0.0382 AC: 107 AN: 2802

East Asian (EAS) AF: 0.00886 AC: 32 AN: 3612

South Asian (SAS) AF: 0.0228 AC: 69 AN: 3028

European-Finnish (FIN) AF: 0.0115 AC: 57 AN: 4954

Middle Eastern (MID) AF: 0.0231 AC: 5 AN: 216

European-Non Finnish (NFE) AF: 0.0214 AC: 1020 AN: 47644

Other (OTH) AF: 0.0173 AC: 25 AN: 1448

Alfa AF: 0.0432 Hom.: 365

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, single submitter

Submissions by phenotype

Niemann-Pick disease, type C1 Benign:3

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

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

- -

Jul 21, 2016

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided Benign:2

-

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Clinical Genetics, Academic Medical Center

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not specified Benign:1

-

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

NPC1-related disorder Benign:1

Apr 12, 2024

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)

Splicing

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

Other links and lift over

dbSNP: rs3837910; hg19: chr18-21124907; COSMIC: COSV52577175; COSMIC: COSV52577175;