NM_001101648.2:c.2638-60T>G

Variant names:

• chr7-44522302-A-C
• rs217420
• NM_001101648.2:c.2638-60T>G

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 12 publications found

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

Our verdict: Benign. The variant received -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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001101648.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NPC1L1	NM_001101648.2	MANE Select	c.2638-60T>G		intron	N/A	NP_001095118.1	A0A0C4DFX6
	NPC1L1	NM_013389.3		c.2638-60T>G		intron	N/A	NP_037521.2	Q9UHC9-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NPC1L1	ENST00000381160.8	TSL:1 MANE Select	c.2638-60T>G		intron	N/A	ENSP00000370552.3	A0A0C4DFX6
	NPC1L1	ENST00000289547.8	TSL:1	c.2638-60T>G		intron	N/A	ENSP00000289547.4	Q9UHC9-1
	NPC1L1	ENST00000546276.5	TSL:1	c.2548-108T>G		intron	N/A	ENSP00000438033.1	A0A0C4DGG6

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

African (AFR) AF: 0.261 AC: 8108 AN: 31096

American (AMR) AF: 0.110 AC: 4225 AN: 38480

Ashkenazi Jewish (ASJ) AF: 0.236 AC: 5897 AN: 24984

East Asian (EAS) AF: 0.00453 AC: 170 AN: 37552

South Asian (SAS) AF: 0.158 AC: 12638 AN: 79766

European-Finnish (FIN) AF: 0.280 AC: 12430 AN: 44354

Middle Eastern (MID) AF: 0.185 AC: 1032 AN: 5578

European-Non Finnish (NFE) AF: 0.247 AC: 253329 AN: 1025464

Other (OTH) AF: 0.226 AC: 12776 AN: 56532

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

African (AFR) AF: 0.254 AC: 10522 AN: 41448

American (AMR) AF: 0.138 AC: 2115 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.248 AC: 862 AN: 3470

East Asian (EAS) AF: 0.00579 AC: 30 AN: 5182

South Asian (SAS) AF: 0.141 AC: 676 AN: 4810

European-Finnish (FIN) AF: 0.289 AC: 3056 AN: 10590

Middle Eastern (MID) AF: 0.150 AC: 44 AN: 294

European-Non Finnish (NFE) AF: 0.248 AC: 16833 AN: 67964

Other (OTH) AF: 0.186 AC: 391 AN: 2102

Alfa AF: 0.240 Hom.: 2407

Bravo AF: 0.217

Asia WGS AF: 0.0940 AC: 328 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	1.5
DANN	Benign	0.52
PhyloP100		-1.2
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs217420; hg19: chr7-44561901;