Genetic Variant CETP:p.Thr8Ser (chr16-56962002-C-G) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_000078.3(CETP):c.23C>G(p.Thr8Ser) 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 1,461,768 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T8N) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000013 ( 1 hom., cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

CETP
NM_000078.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.476

Variant links:

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 links:

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ACMG classification

Classification made for transcript

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=0.03614083).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CETP	NM_000078.3 link	c.23C>G	p.Thr8Ser	missense_variant	Exon 1 of 16	ENST00000200676.8	NP_000069.2	P11597-1A0A0S2Z3F6
CETP	NM_001286085.2 link	c.23C>G	p.Thr8Ser	missense_variant	Exon 1 of 15		NP_001273014.1	A0A0S2Z3I8B4DMZ5
CETP	XM_006721124.4 link	c.23C>G	p.Thr8Ser	missense_variant	Exon 1 of 9		XP_006721187.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
CETP	ENST00000200676.8 link	c.23C>G	p.Thr8Ser	missense_variant	Exon 1 of 16	1	NM_000078.3	ENSP00000200676.3	P11597-1
CETP	ENST00000379780.6 link	c.23C>G	p.Thr8Ser	missense_variant	Exon 1 of 15	1		ENSP00000369106.2	P11597-2
CETP	ENST00000569082.1 link	n.21C>G		non_coding_transcript_exon_variant	Exon 1 of 9	5
CETP	ENST00000566128.1 link	c.-372C>G		upstream_gene_variant		5		ENSP00000456276.1	H3BRJ9

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152214

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.000576

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251168

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135844

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1461768

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

727200

show subpopulations

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

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0000131

AC:

AN:

152214

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74364

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.000576

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.079

BayesDel_addAF

Benign

-0.49

BayesDel_noAF

Benign

-0.85

CADD

Benign

6.5

DANN

Benign

0.83

DEOGEN2

Benign

0.18

T;.

Eigen

Benign

-0.98

Eigen_PC

Benign

-0.89

FATHMM_MKL

Benign

0.013

LIST_S2

Benign

0.37

T;T

M_CAP

Benign

0.011

MetaRNN

Benign

0.036

T;T

MetaSVM

Benign

-0.94

MutationAssessor

Benign

-1.1

N;N

PrimateAI

Benign

0.42

PROVEAN

Benign

-0.52

N;N

REVEL

Benign

0.029

Sift

Benign

0.73

T;T

Sift4G

Benign

0.69

T;T

Polyphen

0.0010

B;B

Vest4

0.035

MutPred

0.33

Gain of disorder (P = 0.0823);Gain of disorder (P = 0.0823);

MVP

0.32

MPC

0.12

ClinPred

0.028

GERP RS

1.3

Varity_R

0.050

gMVP

0.30

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

LitVar

Other links and lift over