rs1800777

chr16-56983407-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000078.3(CETP):c.1403G>A(p.Arg468Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0354 in 1,613,998 control chromosomes in the GnomAD database, including 1,371 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.028 (112 hom., cov: 33)
  • Exomes 𝑓: 0.036 (1259 hom.)
• Consequence: CETP NM_000078.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.358

Genes affected

CETP (HGNC:1869): (cholesteryl ester transfer protein) The protein encoded by this gene is found in plasma, where it is involved in the transfer of cholesteryl ester from high density lipoprotein (HDL) to other lipoproteins. Defects in this gene are a cause of hyperalphalipoproteinemia 1 (HALP1). Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Oct 2013]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0024715066).
• BP6: Variant 16-56983407-G-A is Benign according to our data. Variant chr16-56983407-G-A is described in ClinVar as [Benign]. Clinvar id is 319999.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-56983407-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0671 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CETP	NM_000078.3	c.1403G>A	p.Arg468Gln	missense_variant	15/16	ENST00000200676.8
CETP	NM_001286085.2	c.1223G>A	p.Arg408Gln	missense_variant	14/15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CETP	ENST00000200676.8	c.1403G>A	p.Arg468Gln	missense_variant	15/16	1	NM_000078.3	P1
CETP	ENST00000379780.6	c.1223G>A	p.Arg408Gln	missense_variant	14/15	1
CETP	ENST00000566128.1	c.1208G>A	p.Arg403Gln	missense_variant	15/16	5
CETP	ENST00000650358.1			downstream_gene_variant

Frequencies

GnomAD3 genomes AF: 0.0282 AC: 4291 AN: 152184 Hom.: 110 Cov.: 33

Gnomad AFR AF: 0.00832

Gnomad AMI AF: 0.0230

Gnomad AMR AF: 0.0704

Gnomad ASJ AF: 0.0121

Gnomad EAS AF: 0.000771

Gnomad SAS AF: 0.0317

Gnomad FIN AF: 0.0146

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.0359

Gnomad OTH AF: 0.0239

GnomAD3 exomes AF: 0.0374 AC: 9399 AN: 251464 Hom.: 336 AF XY: 0.0356 AC XY: 4833 AN XY: 135916

Gnomad AFR exome AF: 0.00584

Gnomad AMR exome AF: 0.104

Gnomad ASJ exome AF: 0.00952

Gnomad EAS exome AF: 0.00136

Gnomad SAS exome AF: 0.0330

Gnomad FIN exome AF: 0.0156

Gnomad NFE exome AF: 0.0358

Gnomad OTH exome AF: 0.0288

GnomAD4 exome AF: 0.0362 AC: 52864 AN: 1461696 Hom.: 1259 Cov.: 32 AF XY: 0.0357 AC XY: 25955 AN XY: 727152

Gnomad4 AFR exome AF: 0.00553

Gnomad4 AMR exome AF: 0.0997

Gnomad4 ASJ exome AF: 0.0100

Gnomad4 EAS exome AF: 0.000504

Gnomad4 SAS exome AF: 0.0335

Gnomad4 FIN exome AF: 0.0169

Gnomad4 NFE exome AF: 0.0380

Gnomad4 OTH exome AF: 0.0302

GnomAD4 genome AF: 0.0282 AC: 4297 AN: 152302 Hom.: 112 Cov.: 33 AF XY: 0.0277 AC XY: 2063 AN XY: 74476

Gnomad4 AFR AF: 0.00830

Gnomad4 AMR AF: 0.0706

Gnomad4 ASJ AF: 0.0121

Gnomad4 EAS AF: 0.000773

Gnomad4 SAS AF: 0.0323

Gnomad4 FIN AF: 0.0146

Gnomad4 NFE AF: 0.0359

Gnomad4 OTH AF: 0.0237

Alfa AF: 0.0331 Hom.: 129

Bravo AF: 0.0312

TwinsUK AF: 0.0267 AC: 99

ALSPAC AF: 0.0392 AC: 151

ESP6500AA AF: 0.00842 AC: 37

ESP6500EA AF: 0.0388 AC: 334

ExAC AF: 0.0352 AC: 4279

Asia WGS AF: 0.0130 AC: 46 AN: 3478

EpiCase AF: 0.0328

EpiControl AF: 0.0360

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 25, 2019	This variant is associated with the following publications: (PMID: 24503134, 9253518, 28008009, 27060904, 29987113) -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -

Hyperalphalipoproteinemia 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Mar 06, 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 benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.064
BayesDel_addAF	Benign	-0.81	T
BayesDel_noAF	Benign	-0.86
Cadd	Benign	0.30
Dann	Benign	0.53
DEOGEN2	Benign	0.11	T;.;T
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.0037	N
LIST_S2	Benign	0.73	T;T;T
MetaRNN	Benign	0.0025	T;T;T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	0.28	N;.;.
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.20	T
PROVEAN	Benign	-0.24	N;N;N
REVEL	Benign	0.012
Sift	Benign	0.38	T;T;T
Sift4G	Benign	0.93	T;T;T
Polyphen		0.0030	B;B;.
Vest4		0.036
MPC		0.15
ClinPred		0.0026	T
GERP RS		-5.3
Varity_R		0.046
gMVP		0.33

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: rs1800777; hg19: chr16-57017319; COSMIC: COSV52362452;