rs217420

Positions:

• chr7-44522302-A-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001101648.2(NPC1L1):​c.2638-60T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.231 in 1,495,854 control chromosomes in the GnomAD database, including 42,333 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.23 (4234 hom., cov: 32)
  • Exomes 𝑓: 0.23 (38099 hom.)
• Consequence: NPC1L1 NM_001101648.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.17

Genes affected

NPC1L1 (HGNC:7898): (NPC1 like intracellular cholesterol transporter 1) The protein encoded by this gene is a multi-pass membrane protein. It contains a conserved N-terminal Niemann-Pick C1 (NPC1) domain and a putative sterol-sensing domain (SSD) which includes a YQRL motif functioning as a plasma membrane to trans-Golgi network transport signal in other proteins. This protein takes up free cholesterol into cells through vesicular endocytosis and plays a critical role in the absorption of intestinal cholesterol. It also has the ability to transport alpha-tocopherol (vitamin E). The drug ezetimibe targets this protein and inhibits the absorption of intestinal cholesterol and alpha-tocopherol. In addition, this protein may play a critical role in regulating lipid metabolism. Polymorphic variations in this gene are associated with plasma total cholesterol and low-density lipoprotein cholesterol (LDL-C) levels and coronary heart disease (CHD) risk. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Oct 2009]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.93).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.25 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NPC1L1	NM_001101648.2	c.2638-60T>G		intron_variant		ENST00000381160.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NPC1L1	ENST00000381160.8	c.2638-60T>G		intron_variant		1	NM_001101648.2	P1
NPC1L1	ENST00000289547.8	c.2638-60T>G		intron_variant		1
NPC1L1	ENST00000546276.5	c.2548-108T>G		intron_variant		1

Frequencies

GnomAD3 genomes AF: 0.228 AC: 34627 AN: 151930 Hom.: 4223 Cov.: 32

Gnomad AFR AF: 0.253

Gnomad AMI AF: 0.160

Gnomad AMR AF: 0.139

Gnomad ASJ AF: 0.248

Gnomad EAS AF: 0.00578

Gnomad SAS AF: 0.141

Gnomad FIN AF: 0.289

Gnomad MID AF: 0.139

Gnomad NFE AF: 0.248

Gnomad OTH AF: 0.189

GnomAD4 exome AF: 0.231 AC: 310605 AN: 1343806 Hom.: 38099 AF XY: 0.228 AC XY: 152916 AN XY: 669468

Gnomad4 AFR exome AF: 0.261

Gnomad4 AMR exome AF: 0.110

Gnomad4 ASJ exome AF: 0.236

Gnomad4 EAS exome AF: 0.00453

Gnomad4 SAS exome AF: 0.158

Gnomad4 FIN exome AF: 0.280

Gnomad4 NFE exome AF: 0.247

Gnomad4 OTH exome AF: 0.226

GnomAD4 genome AF: 0.228 AC: 34675 AN: 152048 Hom.: 4234 Cov.: 32 AF XY: 0.224 AC XY: 16672 AN XY: 74318

Gnomad4 AFR AF: 0.254

Gnomad4 AMR AF: 0.138

Gnomad4 ASJ AF: 0.248

Gnomad4 EAS AF: 0.00579

Gnomad4 SAS AF: 0.141

Gnomad4 FIN AF: 0.289

Gnomad4 NFE AF: 0.248

Gnomad4 OTH AF: 0.186

Alfa AF: 0.239 Hom.: 2140

Bravo AF: 0.217

Asia WGS AF: 0.0940 AC: 328 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	1.5
DANN	Benign	0.52

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: rs217420; hg19: chr7-44561901;