18-23544950-C-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

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
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: 0.104

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]

ACMG classification

Verdict is Benign. Variant got -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 [Likely_benign]. Clinvar id is 92702.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr18-23544950-C-G is described in Lovd as [Benign]. Variant chr18-23544950-C-G is described in Lovd as [Likely_benign].
• 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 male gnomad4 subpopulation. Median coverage is 27. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 107 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NPC1	NM_000271.5	c.1947+10G>C		intron_variant		ENST00000269228.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NPC1	ENST00000269228.10	c.1947+10G>C		intron_variant		1	NM_000271.5	P1
NPC1	ENST00000591051.1	c.1025+10G>C		intron_variant		2
NPC1	ENST00000540608.5	n.1861+10G>C		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes AF: 0.00704 AC: 1011 AN: 143684 Hom.: 107 Cov.: 27

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

GnomAD3 exomes AF: 0.00788 AC: 1923 AN: 244166 Hom.: 82 AF XY: 0.00797 AC XY: 1057 AN XY: 132590

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 SAS exome AF: 0.00423

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.: 26 AF XY: 0.00886 AC XY: 5669 AN XY: 640090

Gnomad4 AFR exome AF: 0.00102

Gnomad4 AMR exome AF: 0.00170

Gnomad4 ASJ exome AF: 0.000359

Gnomad4 EAS exome AF: 0.0000289

Gnomad4 SAS exome AF: 0.00476

Gnomad4 FIN exome AF: 0.0238

Gnomad4 NFE exome AF: 0.00995

Gnomad4 OTH exome AF: 0.00643

GnomAD4 genome AF: 0.00704 AC: 1012 AN: 143798 Hom.: 107 Cov.: 27 AF XY: 0.00740 AC XY: 521 AN XY: 70358

Gnomad4 AFR AF: 0.00126

Gnomad4 AMR AF: 0.00270

Gnomad4 ASJ AF: 0.00149

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00418

Gnomad4 FIN AF: 0.0226

Gnomad4 NFE AF: 0.0104

Gnomad4 OTH AF: 0.00355

Alfa AF: 0.00454 Hom.: 17

Bravo AF: 0.00467

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Niemann-Pick disease, type C1 Benign:6

Likely benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	Jun 20, 2016	- -
Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	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. -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Oct 21, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Jan 17, 2022	- -

not specified Benign:3

Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 22, 2013	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2024	NPC1: BS1, BS2 -
Likely benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	May 10, 2017	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
Cadd	Benign	0.53
Dann	Benign	0.30

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

LitVar

Other links and lift over

dbSNP: rs71534236; hg19: chr18-21124914;