NM_000078.3:c.44C>G

Variant names:

• chr16-56962023-C-G
• rs34065661
• NM_000078.3:c.44C>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000078.3(CETP):​c.44C>G​(p.Ala15Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00404 in 1,614,066 control chromosomes in the GnomAD database, including 202 homozygotes. 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 Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A15S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.020 (115 hom., cov: 32)
  • Exomes 𝑓: 0.0024 (87 hom.)
• Consequence: CETP NM_000078.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.173
• Publications: 26 publications found

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]

CETP Gene-Disease associations (from GenCC):

• cholesterol-ester transfer protein deficiency

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.001814127).
• BP6: Variant 16-56962023-C-G is Benign according to our data. Variant chr16-56962023-C-G is described in ClinVar as [Benign]. Clinvar id is 319970.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0654 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CETP	NM_000078.3	c.44C>G	p.Ala15Gly	missense_variant	Exon 1 of 16	ENST00000200676.8	NP_000069.2
CETP	NM_001286085.2	c.44C>G	p.Ala15Gly	missense_variant	Exon 1 of 15		NP_001273014.1
CETP	XM_006721124.4	c.44C>G	p.Ala15Gly	missense_variant	Exon 1 of 9		XP_006721187.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CETP	ENST00000200676.8	c.44C>G	p.Ala15Gly	missense_variant	Exon 1 of 16	1	NM_000078.3	ENSP00000200676.3
CETP	ENST00000379780.6	c.44C>G	p.Ala15Gly	missense_variant	Exon 1 of 15	1		ENSP00000369106.2
CETP	ENST00000569082.1	n.42C>G		non_coding_transcript_exon_variant	Exon 1 of 9	5
CETP	ENST00000566128.1	c.-351C>G		upstream_gene_variant		5		ENSP00000456276.1

Frequencies

GnomAD3 genomes AF: 0.0201 AC: 3057 AN: 152202 Hom.: 115 Cov.: 32

Gnomad AFR AF: 0.0672

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0115

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.000764

Gnomad OTH AF: 0.0153

GnomAD2 exomes AF: 0.00526 AC: 1322 AN: 251122 AF XY: 0.00387

Gnomad AFR exome AF: 0.0658

Gnomad AMR exome AF: 0.00419

Gnomad ASJ exome AF: 0.00119

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000464

Gnomad NFE exome AF: 0.000581

Gnomad OTH exome AF: 0.00391

GnomAD4 exome AF: 0.00235 AC: 3442 AN: 1461746 Hom.: 87 Cov.: 31 AF XY: 0.00204 AC XY: 1482 AN XY: 727186

African (AFR) AF: 0.0683 AC: 2287 AN: 33470

American (AMR) AF: 0.00494 AC: 221 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00172 AC: 45 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.000197 AC: 17 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53302

Middle Eastern (MID) AF: 0.00798 AC: 46 AN: 5768

European-Non Finnish (NFE) AF: 0.000446 AC: 496 AN: 1111996

Other (OTH) AF: 0.00546 AC: 330 AN: 60392

GnomAD4 genome AF: 0.0202 AC: 3075 AN: 152320 Hom.: 115 Cov.: 32 AF XY: 0.0203 AC XY: 1509 AN XY: 74492

African (AFR) AF: 0.0675 AC: 2804 AN: 41564

American (AMR) AF: 0.0114 AC: 175 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00173 AC: 6 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4832

European-Finnish (FIN) AF: 0.0000941 AC: 1 AN: 10624

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.000764 AC: 52 AN: 68022

Other (OTH) AF: 0.0152 AC: 32 AN: 2110

Alfa AF: 0.00176 Hom.: 1

Bravo AF: 0.0230

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.0648 AC: 285

ESP6500EA AF: 0.000930 AC: 8

ExAC AF: 0.00651 AC: 791

Asia WGS AF: 0.00606 AC: 22 AN: 3478

EpiCase AF: 0.000545

EpiControl AF: 0.000771

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Jan 29, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Apr 21, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 26683795) -

Hyperalphalipoproteinemia 1 Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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	0.079
BayesDel_addAF	Benign	-0.71	T
BayesDel_noAF	Benign	-0.75
CADD	Benign	6.2
DANN	Benign	0.86
DEOGEN2	Benign	0.31	T;.
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.022	N
LIST_S2	Benign	0.57	T;T
MetaRNN	Benign	0.0018	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.8	L;L
PhyloP100		-0.17
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-1.8	N;N
REVEL	Benign	0.013
Sift	Benign	0.032	D;D
Sift4G	Benign	0.075	T;T
Polyphen		0.084	B;B
Vest4		0.084
MVP		0.32
MPC		0.16
ClinPred		0.0018	T
GERP RS		-0.44
PromoterAI		0.097	Neutral
Varity_R		0.072
gMVP		0.41
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs34065661; hg19: chr16-56995935;