16-56983367-G-C

Variant names:

• chr16-56983367-G-C
• rs2228667
• NM_000078.3:c.1363G>C

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_000078.3(CETP):​c.1363G>C​(p.Val455Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/22 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 nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V455M) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: CETP NM_000078.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.21
• Publications: 3 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.06525597).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000078.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CETP	NM_000078.3	MANE Select	c.1363G>C	p.Val455Leu	missense	Exon 15 of 16	NP_000069.2	P11597-1
	CETP	NM_001286085.2		c.1183G>C	p.Val395Leu	missense	Exon 14 of 15	NP_001273014.1	A0A0S2Z3I8

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CETP	ENST00000200676.8	TSL:1 MANE Select	c.1363G>C	p.Val455Leu	missense	Exon 15 of 16	ENSP00000200676.3	P11597-1
	CETP	ENST00000379780.6	TSL:1	c.1183G>C	p.Val395Leu	missense	Exon 14 of 15	ENSP00000369106.2	P11597-2
	CETP	ENST00000858282.1		c.1471G>C	p.Val491Leu	missense	Exon 16 of 17	ENSP00000528341.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.062
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.72
CADD	Benign	5.3
DANN	Benign	0.53
DEOGEN2	Benign	0.10	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-0.89
FATHMM_MKL	Benign	0.0075	N
LIST_S2	Benign	0.46	T
M_CAP	Uncertain	0.087	D
MetaRNN	Benign	0.065	T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	-2.1	N
PhyloP100		2.2
PrimateAI	Benign	0.39	T
PROVEAN	Benign	0.55	N
REVEL	Benign	0.049
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.088
MutPred		0.58		Loss of ubiquitination at K453 (P = 0.0653)
MVP		0.13
MPC		0.13
ClinPred		0.031	T
GERP RS		3.2
Varity_R		0.097
gMVP		0.31

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: rs2228667; hg19: chr16-57017279;