rs1532625

chr16-56971389-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000078.3(CETP):c.658+8C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.417 in 1,611,616 control chromosomes in the GnomAD database, including 144,548 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/2 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.34 (10314 hom., cov: 32)
  • Exomes 𝑓: 0.42 (134234 hom.)
• Consequence: CETP NM_000078.3 splice_region, intron
• Scores: Splicing: ADA: 0.0001526
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.729

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 16-56971389-C-T is Benign according to our data. Variant chr16-56971389-C-T is described in ClinVar as [Benign]. Clinvar id is 319981.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-56971389-C-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.46 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CETP	NM_000078.3	c.658+8C>T		splice_region_variant, intron_variant		ENST00000200676.8
CETP	NM_001286085.2	c.658+8C>T		splice_region_variant, intron_variant
CETP	XM_006721124.4	c.658+8C>T		splice_region_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CETP	ENST00000200676.8	c.658+8C>T		splice_region_variant, intron_variant		1	NM_000078.3	P1
CETP	ENST00000379780.6	c.658+8C>T		splice_region_variant, intron_variant		1
CETP	ENST00000566128.1	c.463+8C>T		splice_region_variant, intron_variant		5
CETP	ENST00000569082.1	n.760+8C>T		splice_region_variant, intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.344 AC: 52308 AN: 151928 Hom.: 10319 Cov.: 32

Gnomad AFR AF: 0.149

Gnomad AMI AF: 0.525

Gnomad AMR AF: 0.344

Gnomad ASJ AF: 0.390

Gnomad EAS AF: 0.283

Gnomad SAS AF: 0.475

Gnomad FIN AF: 0.422

Gnomad MID AF: 0.380

Gnomad NFE AF: 0.442

Gnomad OTH AF: 0.344

GnomAD3 exomes AF: 0.397 AC: 99581 AN: 250894 Hom.: 20498 AF XY: 0.408 AC XY: 55331 AN XY: 135628

Gnomad AFR exome AF: 0.145

Gnomad AMR exome AF: 0.372

Gnomad ASJ exome AF: 0.386

Gnomad EAS exome AF: 0.291

Gnomad SAS exome AF: 0.475

Gnomad FIN exome AF: 0.413

Gnomad NFE exome AF: 0.434

Gnomad OTH exome AF: 0.410

GnomAD4 exome AF: 0.425 AC: 620048 AN: 1459570 Hom.: 134234 Cov.: 35 AF XY: 0.428 AC XY: 310766 AN XY: 726270

Gnomad4 AFR exome AF: 0.141

Gnomad4 AMR exome AF: 0.366

Gnomad4 ASJ exome AF: 0.387

Gnomad4 EAS exome AF: 0.290

Gnomad4 SAS exome AF: 0.481

Gnomad4 FIN exome AF: 0.419

Gnomad4 NFE exome AF: 0.438

Gnomad4 OTH exome AF: 0.408

GnomAD4 genome AF: 0.344 AC: 52298 AN: 152046 Hom.: 10314 Cov.: 32 AF XY: 0.346 AC XY: 25737 AN XY: 74316

Gnomad4 AFR AF: 0.148

Gnomad4 AMR AF: 0.344

Gnomad4 ASJ AF: 0.390

Gnomad4 EAS AF: 0.283

Gnomad4 SAS AF: 0.476

Gnomad4 FIN AF: 0.422

Gnomad4 NFE AF: 0.442

Gnomad4 OTH AF: 0.340

Alfa AF: 0.380 Hom.: 5948

Bravo AF: 0.327

Asia WGS AF: 0.351 AC: 1221 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 30, 2018	- -

Hyperalphalipoproteinemia 1 Benign:2

Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 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 specified Benign:1

Benign, no assertion criteria provided

clinical testing

Clinical Genetics, Academic Medical Center

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
Cadd	Benign	0.76
Dann	Benign	0.77

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00015
dbscSNV1_RF	Benign	0.0
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: rs1532625; hg19: chr16-57005301; COSMIC: COSV52363738;