16-56981633-C-T

Position:

• chr16-56981633-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.1215-14C>T variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.339 in 1,610,056 control chromosomes in the GnomAD database, including 95,517 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.32 (8055 hom., cov: 32)
  • Exomes 𝑓: 0.34 (87462 hom.)
• Consequence: CETP NM_000078.3 splice_polypyrimidine_tract, intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.579

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=-0.77).
• BP6: Variant 16-56981633-C-T is Benign according to our data. Variant chr16-56981633-C-T is described in ClinVar as [Benign]. Clinvar id is 319995.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-56981633-C-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.359 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CETP	NM_000078.3	c.1215-14C>T		splice_polypyrimidine_tract_variant, intron_variant		ENST00000200676.8	NP_000069.2
CETP	NM_001286085.2	c.1035-14C>T		splice_polypyrimidine_tract_variant, intron_variant			NP_001273014.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CETP	ENST00000200676.8	c.1215-14C>T		splice_polypyrimidine_tract_variant, intron_variant		1	NM_000078.3	ENSP00000200676	P1
CETP	ENST00000379780.6	c.1035-14C>T		splice_polypyrimidine_tract_variant, intron_variant		1		ENSP00000369106
CETP	ENST00000566128.1	c.1020-14C>T		splice_polypyrimidine_tract_variant, intron_variant		5		ENSP00000456276
CETP	ENST00000650358.1	n.1613-14C>T		splice_polypyrimidine_tract_variant, intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.318 AC: 48282 AN: 151982 Hom.: 8051 Cov.: 32

Gnomad AFR AF: 0.270

Gnomad AMI AF: 0.266

Gnomad AMR AF: 0.332

Gnomad ASJ AF: 0.285

Gnomad EAS AF: 0.127

Gnomad SAS AF: 0.312

Gnomad FIN AF: 0.304

Gnomad MID AF: 0.294

Gnomad NFE AF: 0.363

Gnomad OTH AF: 0.315

GnomAD3 exomes AF: 0.320 AC: 80337 AN: 251354 Hom.: 13387 AF XY: 0.324 AC XY: 44071 AN XY: 135864

Gnomad AFR exome AF: 0.266

Gnomad AMR exome AF: 0.327

Gnomad ASJ exome AF: 0.284

Gnomad EAS exome AF: 0.135

Gnomad SAS exome AF: 0.330

Gnomad FIN exome AF: 0.300

Gnomad NFE exome AF: 0.359

Gnomad OTH exome AF: 0.312

GnomAD4 exome AF: 0.342 AC: 498030 AN: 1457956 Hom.: 87462 Cov.: 34 AF XY: 0.342 AC XY: 247775 AN XY: 725516

Gnomad4 AFR exome AF: 0.268

Gnomad4 AMR exome AF: 0.329

Gnomad4 ASJ exome AF: 0.281

Gnomad4 EAS exome AF: 0.0983

Gnomad4 SAS exome AF: 0.333

Gnomad4 FIN exome AF: 0.304

Gnomad4 NFE exome AF: 0.358

Gnomad4 OTH exome AF: 0.330

GnomAD4 genome AF: 0.318 AC: 48299 AN: 152100 Hom.: 8055 Cov.: 32 AF XY: 0.314 AC XY: 23362 AN XY: 74364

Gnomad4 AFR AF: 0.269

Gnomad4 AMR AF: 0.332

Gnomad4 ASJ AF: 0.285

Gnomad4 EAS AF: 0.127

Gnomad4 SAS AF: 0.313

Gnomad4 FIN AF: 0.304

Gnomad4 NFE AF: 0.363

Gnomad4 OTH AF: 0.311

Alfa AF: 0.330 Hom.: 5065

Bravo AF: 0.314

Asia WGS AF: 0.212 AC: 740 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 30, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

Hyperalphalipoproteinemia 1 Benign:1

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	7.4
DANN	Benign	0.70

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs1800774; hg19: chr16-57015545; COSMIC: COSV52361521;