rs2303790

Positions:

• chr16-56983380-A-G

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_000078.3(CETP):​c.1376A>G​(p.Asp459Gly) variant causes a missense change. The variant allele was found at a frequency of 0.00105 in 1,614,202 control chromosomes in the GnomAD database, including 27 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D459H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0010 (6 hom., cov: 33)
  • Exomes 𝑓: 0.0011 (21 hom.)
• Consequence: CETP NM_000078.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1 B:1
• Conservation: PhyloP100: 4.23

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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.006863296).
• BP6: Variant 16-56983380-A-G is Benign according to our data. Variant chr16-56983380-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 17527.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Benign=1}. Variant chr16-56983380-A-G is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.001 (153/152320) while in subpopulation EAS AF= 0.0271 (140/5168). AF 95% confidence interval is 0.0234. There are 6 homozygotes in gnomad4. There are 90 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 6 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CETP	NM_000078.3	c.1376A>G	p.Asp459Gly	missense_variant	15/16	ENST00000200676.8
CETP	NM_001286085.2	c.1196A>G	p.Asp399Gly	missense_variant	14/15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CETP	ENST00000200676.8	c.1376A>G	p.Asp459Gly	missense_variant	15/16	1	NM_000078.3	P1
CETP	ENST00000379780.6	c.1196A>G	p.Asp399Gly	missense_variant	14/15	1
CETP	ENST00000566128.1	c.1181A>G	p.Asp394Gly	missense_variant	15/16	5
CETP	ENST00000650358.1	n.1774A>G		non_coding_transcript_exon_variant	5/5

Frequencies

GnomAD3 genomes AF: 0.00101 AC: 154 AN: 152202 Hom.: 6 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0272

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.000377

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00257 AC: 646 AN: 251456 Hom.: 8 AF XY: 0.00234 AC XY: 318 AN XY: 135908

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000578

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0331

Gnomad SAS exome AF: 0.000229

Gnomad FIN exome AF: 0.000277

Gnomad NFE exome AF: 0.000149

Gnomad OTH exome AF: 0.000978

GnomAD4 exome AF: 0.00106 AC: 1544 AN: 1461882 Hom.: 21 Cov.: 32 AF XY: 0.00104 AC XY: 755 AN XY: 727242

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0341

Gnomad4 SAS exome AF: 0.000151

Gnomad4 FIN exome AF: 0.000393

Gnomad4 NFE exome AF: 0.0000809

Gnomad4 OTH exome AF: 0.00103

GnomAD4 genome AF: 0.00100 AC: 153 AN: 152320 Hom.: 6 Cov.: 33 AF XY: 0.00121 AC XY: 90 AN XY: 74484

Gnomad4 AFR AF: 0.0000240

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0271

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.000377

Gnomad4 NFE AF: 0.0000882

Gnomad4 OTH AF: 0.00

Alfa AF: 0.00104 Hom.: 4

Bravo AF: 0.00122

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.00239 AC: 290

Asia WGS AF: 0.0130 AC: 45 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hyperalphalipoproteinemia 1 Pathogenic:1 Benign:1

Pathogenic, no assertion criteria provided	literature only	OMIM	Apr 24, 1995	- -
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. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Jun 26, 2023

Reported as a common variant in the East Asian population and is associated with increased HDL-C levels; however, this variant is not associated with decreased LDL-C levels and there is no evidence of a cardioprotective effect (Takahashi et al., 1993; Inazu et al., 1994; Thompson et al., 2009; Khovidhunkit et al., 2012; Millwood et al., 2018); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Functional studies demonstrate that this variant leads to a decrease of CETP activity (Takahashi et al., 1993; Thompson et al., 2009); This variant is associated with the following publications: (PMID: 24497850, 28173125, 8408659, 27516387, 18468607, 25525159, 27896098, 7962532, 25629512, 19444232, 26690388, 29083407, 22464213, 21354572, 27659420, 29141072, 9116424, 31180159, 33358712, 20981092, 12482565, 34426522, 7605382, 7989465, 35174233, 34011801) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.53	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.34	T;.;T
Eigen	Benign	-0.17
Eigen_PC	Benign	-0.15
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Uncertain	0.87	D;T;D
MetaRNN	Benign	0.0069	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	2.0	M;.;.
MutationTaster	Benign	0.66	N;N;N
PrimateAI	Benign	0.36	T
PROVEAN	Uncertain	-3.7	D;N;D
REVEL	Benign	0.13
Sift	Uncertain	0.016	D;D;D
Sift4G	Uncertain	0.0080	D;D;D
Polyphen		0.58	P;B;.
Vest4		0.61
MVP		0.51
MPC		0.52
ClinPred		0.071	T
GERP RS		3.2
Varity_R		0.30
gMVP		0.63

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: rs2303790; hg19: chr16-57017292;