Genetic Variant NM_001101648.2:c.816C>G (chr7-44539581-G-C) – ACMG Classification: Benign (-15 pts)

Variant summary

Our verdict is Benign. The variant received -15 ACMG points: 0P and 15B. BP4_StrongBP6_ModerateBP7BA1

The NM_001101648.2(NPC1L1):c.816C>G(p.Leu272Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.233 in 1,613,858 control chromosomes in the GnomAD database, including 45,308 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.24 ( 4483 hom., cov: 33)

Exomes 𝑓: 0.23 ( 40825 hom. )

Consequence

NPC1L1
NM_001101648.2 synonymous

Scores

Clinical Significance

Benign criteria provided, single submitter B:1O:1

Conservation

PhyloP100: 1.15

Publications

120 publications found

Variant links:

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]

NPC1L1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -15 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.83).

BP6

Variant 7-44539581-G-C is Benign according to our data. Variant chr7-44539581-G-C is described in ClinVar as Benign. ClinVar VariationId is 403258.Status of the report is criteria_provided_single_submitter, 1 stars.

BP7

Synonymous conserved (PhyloP=1.15 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.361 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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
NPC1L1	NM_001101648.2	MANE Select	c.816C>G	p.Leu272Leu	synonymous	Exon 2 of 19	NP_001095118.1
NPC1L1	NM_013389.3		c.816C>G	p.Leu272Leu	synonymous	Exon 2 of 20	NP_037521.2
NPC1L1	NM_001300967.2		c.816C>G	p.Leu272Leu	synonymous	Exon 2 of 7	NP_001287896.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
NPC1L1	ENST00000381160.8	TSL:1 MANE Select	c.816C>G	p.Leu272Leu	synonymous	Exon 2 of 19	ENSP00000370552.3
NPC1L1	ENST00000289547.8	TSL:1	c.816C>G	p.Leu272Leu	synonymous	Exon 2 of 20	ENSP00000289547.4
NPC1L1	ENST00000546276.5	TSL:1	c.816C>G	p.Leu272Leu	synonymous	Exon 2 of 18	ENSP00000438033.1

Frequencies

GnomAD3 genomes

AF:

0.236

AC:

35859

AN:

152028

Hom.:

4472

Cov.:

show subpopulations

Gnomad AFR

AF:

0.206

Gnomad AMI

AF:

0.114

Gnomad AMR

AF:

0.227

Gnomad ASJ

AF:

0.221

Gnomad EAS

AF:

0.375

Gnomad SAS

AF:

0.214

Gnomad FIN

AF:

0.368

Gnomad MID

AF:

0.165

Gnomad NFE

AF:

0.230

Gnomad OTH

AF:

0.206

GnomAD2 exomes

AF:

0.249

AC:

62483

AN:

250938

AF XY:

0.245

show subpopulations

Gnomad AFR exome

AF:

0.209

Gnomad AMR exome

AF:

0.254

Gnomad ASJ exome

AF:

0.204

Gnomad EAS exome

AF:

0.364

Gnomad FIN exome

AF:

0.369

Gnomad NFE exome

AF:

0.228

Gnomad OTH exome

AF:

0.231

GnomAD4 exome

AF:

0.232

AC:

339457

AN:

1461712

Hom.:

40825

Cov.:

AF XY:

0.231

AC XY:

168147

AN XY:

727134

show subpopulations

African (AFR)

AF:

0.212

AC:

7086

AN:

33480

American (AMR)

AF:

0.249

AC:

11148

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.211

AC:

5520

AN:

26132

East Asian (EAS)

AF:

0.374

AC:

14847

AN:

39700

South Asian (SAS)

AF:

0.206

AC:

17743

AN:

86252

European-Finnish (FIN)

AF:

0.359

AC:

19138

AN:

53270

Middle Eastern (MID)

AF:

0.166

AC:

960

AN:

5768

European-Non Finnish (NFE)

AF:

0.224

AC:

248981

AN:

1112000

Other (OTH)

AF:

0.232

AC:

14034

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.484

Heterozygous variant carriers

17983

35966

53948

71931

89914

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

8670

17340

26010

34680

43350

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.236

AC:

35902

AN:

152146

Hom.:

4483

Cov.:

AF XY:

0.244

AC XY:

18129

AN XY:

74364

show subpopulations

African (AFR)

AF:

0.206

AC:

8567

AN:

41522

American (AMR)

AF:

0.228

AC:

3487

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.221

AC:

767

AN:

3468

East Asian (EAS)

AF:

0.375

AC:

1939

AN:

5174

South Asian (SAS)

AF:

0.214

AC:

1032

AN:

4818

European-Finnish (FIN)

AF:

0.368

AC:

3901

AN:

10588

Middle Eastern (MID)

AF:

0.167

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.230

AC:

15610

AN:

67958

Other (OTH)

AF:

0.211

AC:

446

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1420

2840

4261

5681

7101

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

380

760

1140

1520

1900

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.231

Hom.:

3184

Bravo

AF:

0.225

Asia WGS

AF:

0.298

AC:

1035

AN:

3478

EpiCase

AF:

0.214

EpiControl

AF:

0.219

ClinVar

Significance: Benign

Submissions summary: Benign:1Other:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Benign:1

Mar 29, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency

Statins, attenuated cholesterol lowering by

Other:1

Nov 01, 2022

Department of Cardiology, Chinese Academy of Medical Sciences, Fuwai Hospital

Significance:drug response

Review Status:no assertion criteria provided

Collection Method:research

likely responsive

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.83

CADD

Benign

1.5

(source)

DANN

Benign

0.43

PhyloP100

1.1

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over