rs5882

chr16-56982180-G-Achr16-56982180-G-C

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.1264G>A(p.Val422Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.652 in 1,613,398 control chromosomes in the GnomAD database, including 346,892 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.59 (27578 hom., cov: 31)
  • Exomes 𝑓: 0.66 (319314 hom.)
• Consequence: CETP NM_000078.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6 O:1
• Conservation: PhyloP100: -2.36

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=3.5843727E-6).
• BP6: Variant 16-56982180-G-A is Benign according to our data. Variant chr16-56982180-G-A is described in ClinVar as [Benign]. Clinvar id is 17525.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-56982180-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.678 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CETP	NM_000078.3	c.1264G>A	p.Val422Ile	missense_variant	14/16	ENST00000200676.8
CETP	NM_001286085.2	c.1084G>A	p.Val362Ile	missense_variant	13/15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CETP	ENST00000200676.8	c.1264G>A	p.Val422Ile	missense_variant	14/16	1	NM_000078.3	P1
CETP	ENST00000379780.6	c.1084G>A	p.Val362Ile	missense_variant	13/15	1
CETP	ENST00000566128.1	c.1069G>A	p.Val357Ile	missense_variant	14/16	5
CETP	ENST00000650358.1	n.1662G>A		non_coding_transcript_exon_variant	4/5

Frequencies

GnomAD3 genomes AF: 0.590 AC: 89567 AN: 151834 Hom.: 27562 Cov.: 31

Gnomad AFR AF: 0.425

Gnomad AMI AF: 0.460

Gnomad AMR AF: 0.627

Gnomad ASJ AF: 0.585

Gnomad EAS AF: 0.555

Gnomad SAS AF: 0.563

Gnomad FIN AF: 0.622

Gnomad MID AF: 0.576

Gnomad NFE AF: 0.683

Gnomad OTH AF: 0.620

GnomAD3 exomes AF: 0.619 AC: 155510 AN: 251372 Hom.: 48877 AF XY: 0.624 AC XY: 84847 AN XY: 135866

Gnomad AFR exome AF: 0.418

Gnomad AMR exome AF: 0.586

Gnomad ASJ exome AF: 0.592

Gnomad EAS exome AF: 0.554

Gnomad SAS exome AF: 0.567

Gnomad FIN exome AF: 0.621

Gnomad NFE exome AF: 0.684

Gnomad OTH exome AF: 0.617

GnomAD4 exome AF: 0.658 AC: 961601 AN: 1461446 Hom.: 319314 Cov.: 53 AF XY: 0.656 AC XY: 477060 AN XY: 727052

Gnomad4 AFR exome AF: 0.411

Gnomad4 AMR exome AF: 0.592

Gnomad4 ASJ exome AF: 0.589

Gnomad4 EAS exome AF: 0.520

Gnomad4 SAS exome AF: 0.569

Gnomad4 FIN exome AF: 0.617

Gnomad4 NFE exome AF: 0.685

Gnomad4 OTH exome AF: 0.638

GnomAD4 genome AF: 0.590 AC: 89617 AN: 151952 Hom.: 27578 Cov.: 31 AF XY: 0.586 AC XY: 43572 AN XY: 74296

Gnomad4 AFR AF: 0.425

Gnomad4 AMR AF: 0.627

Gnomad4 ASJ AF: 0.585

Gnomad4 EAS AF: 0.555

Gnomad4 SAS AF: 0.563

Gnomad4 FIN AF: 0.622

Gnomad4 NFE AF: 0.683

Gnomad4 OTH AF: 0.619

Alfa AF: 0.657 Hom.: 81813

Bravo AF: 0.580

TwinsUK AF: 0.687 AC: 2549

ALSPAC AF: 0.676 AC: 2605

ESP6500AA AF: 0.415 AC: 1823

ESP6500EA AF: 0.681 AC: 5860

ExAC AF: 0.616 AC: 74827

Asia WGS AF: 0.533 AC: 1857 AN: 3478

EpiCase AF: 0.682

EpiControl AF: 0.672

ClinVar

Significance: Benign

Submissions summary: Benign:6 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 30, 2018	This variant is associated with the following publications: (PMID: 10092998, 23977315, 25260850, 22464147, 21767357, 20068209, 14559957, 19242900, 23274582, 22122979) -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

Hyperalphalipoproteinemia 1 Benign:2

Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -

not specified Benign:1

Benign, no assertion criteria provided

clinical testing

Clinical Genetics, Academic Medical Center

-

- -

Coronary artery disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

Rasad Genetic Department, Rasad Pathobiology and Genetic Laboratory

May 12, 2022

- -

High density lipoprotein cholesterol level quantitative trait locus 10 Other:1

association, no assertion criteria provided

literature only

OMIM

Jan 13, 2010

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.068
BayesDel_addAF	Benign	-0.88	T
BayesDel_noAF	Benign	-0.89
Cadd	Benign	0.0010
Dann	Benign	0.24
DEOGEN2	Benign	0.070	T;.;T
Eigen	Benign	-1.7
Eigen_PC	Benign	-1.8
FATHMM_MKL	Benign	0.0043	N
LIST_S2	Benign	0.50	T;T;T
MetaRNN	Benign	0.0000036	T;T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	-0.57	N;.;.
MutationTaster	Benign	1.0	P;P;P
PrimateAI	Benign	0.29	T
PROVEAN	Benign	0.52	N;N;N
REVEL	Benign	0.013
Sift	Benign	1.0	T;T;T
Sift4G	Benign	1.0	T;T;T
Polyphen		0.0010	B;B;.
Vest4		0.028
MPC		0.11
ClinPred		0.0086	T
GERP RS		-6.7
Varity_R		0.017
gMVP		0.088

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs5882; hg19: chr16-57016092; COSMIC: COSV52364598;