chr16-56963017-C-G

Position:

• chr16-56963017-C-G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_000078.3(CETP):​c.126C>G​(p.His42Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,748 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: CETP NM_000078.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.56

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 Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.06406245).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CETP	NM_000078.3	c.126C>G	p.His42Gln	missense_variant	2/16	ENST00000200676.8	NP_000069.2
CETP	NM_001286085.2	c.126C>G	p.His42Gln	missense_variant	2/15		NP_001273014.1
CETP	XM_006721124.4	c.126C>G	p.His42Gln	missense_variant	2/9		XP_006721187.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CETP	ENST00000200676.8	c.126C>G	p.His42Gln	missense_variant	2/16	1	NM_000078.3	ENSP00000200676	P1
CETP	ENST00000379780.6	c.126C>G	p.His42Gln	missense_variant	2/15	1		ENSP00000369106
CETP	ENST00000566128.1	c.-70C>G		5_prime_UTR_variant	2/16	5		ENSP00000456276
CETP	ENST00000569082.1	n.124C>G		non_coding_transcript_exon_variant	2/9	5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461748 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 727180

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

May 17, 2023

This sequence change replaces histidine, which is basic and polar, with glutamine, which is neutral and polar, at codon 42 of the CETP protein (p.His42Gln). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt CETP protein function. This variant has not been reported in the literature in individuals affected with CETP-related conditions. This variant is not present in population databases (gnomAD no frequency). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.047
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.75
CADD	Benign	3.8
DANN	Benign	0.22
DEOGEN2	Benign	0.098	T;.
Eigen	Benign	-1.7
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.016	N
LIST_S2	Benign	0.32	T;T
M_CAP	Benign	0.050	D
MetaRNN	Benign	0.064	T;T
MetaSVM	Benign	-0.88	T
MutationAssessor	Benign	-2.2	N;N
MutationTaster	Benign	1.0	D;N;N
PrimateAI	Benign	0.29	T
PROVEAN	Benign	3.2	N;N
REVEL	Benign	0.12
Sift	Benign	1.0	T;T
Sift4G	Benign	0.95	T;T
Polyphen		0.0	B;B
Vest4		0.19
MutPred		0.31		Loss of catalytic residue at H42 (P = 0.0337);Loss of catalytic residue at H42 (P = 0.0337);
MVP		0.18
MPC		0.13
ClinPred		0.078	T
GERP RS		-1.9
Varity_R		0.12
gMVP		0.17

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.12		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr16-56996929;