rs5884

Variant names:

• chr16-56962045-C-A
• rs5884
• NM_000078.3:c.66C>A

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_000078.3(CETP):​c.66C>A​(p.Thr22Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00276 in 1,614,142 control chromosomes in the GnomAD database, including 79 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.014 (42 hom., cov: 32)
  • Exomes 𝑓: 0.0016 (37 hom.)
• Consequence: CETP NM_000078.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 1.29
• Publications: 11 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.73).
• BP6: Variant 16-56962045-C-A is Benign according to our data. Variant chr16-56962045-C-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 319971.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.29 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.014 (2135/152334) while in subpopulation AFR AF = 0.0478 (1987/41564). AF 95% confidence interval is 0.0461. There are 42 homozygotes in GnomAd4. There are 1011 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 2135 AD gene.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CETP	NM_000078.3	MANE Select	c.66C>A	p.Thr22Thr	synonymous	Exon 1 of 16	NP_000069.2
	CETP	NM_001286085.2		c.66C>A	p.Thr22Thr	synonymous	Exon 1 of 15	NP_001273014.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CETP	ENST00000200676.8	TSL:1 MANE Select	c.66C>A	p.Thr22Thr	synonymous	Exon 1 of 16	ENSP00000200676.3
	CETP	ENST00000379780.6	TSL:1	c.66C>A	p.Thr22Thr	synonymous	Exon 1 of 15	ENSP00000369106.2
	CETP	ENST00000569082.1	TSL:5	n.64C>A		non_coding_transcript_exon	Exon 1 of 9

Frequencies

GnomAD3 genomes AF: 0.0140 AC: 2129 AN: 152216 Hom.: 42 Cov.: 32

Gnomad AFR AF: 0.0478

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00713

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.000250

Gnomad OTH AF: 0.00717

GnomAD2 exomes AF: 0.00362 AC: 910 AN: 251134 AF XY: 0.00271

Gnomad AFR exome AF: 0.0473

Gnomad AMR exome AF: 0.00289

Gnomad ASJ exome AF: 0.0000993

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000211

Gnomad OTH exome AF: 0.00212

GnomAD4 exome AF: 0.00159 AC: 2323 AN: 1461808 Hom.: 37 Cov.: 31 AF XY: 0.00143 AC XY: 1039 AN XY: 727212

African (AFR) AF: 0.0498 AC: 1668 AN: 33476

American (AMR) AF: 0.00349 AC: 156 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26136

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

South Asian (SAS) AF: 0.000139 AC: 12 AN: 86252

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53354

Middle Eastern (MID) AF: 0.00537 AC: 31 AN: 5768

European-Non Finnish (NFE) AF: 0.000197 AC: 219 AN: 1112002

Other (OTH) AF: 0.00391 AC: 236 AN: 60396

GnomAD4 genome AF: 0.0140 AC: 2135 AN: 152334 Hom.: 42 Cov.: 32 AF XY: 0.0136 AC XY: 1011 AN XY: 74494

African (AFR) AF: 0.0478 AC: 1987 AN: 41564

American (AMR) AF: 0.00712 AC: 109 AN: 15312

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.0170 AC: 5 AN: 294

European-Non Finnish (NFE) AF: 0.000250 AC: 17 AN: 68026

Other (OTH) AF: 0.00710 AC: 15 AN: 2114

Alfa AF: 0.00572 Hom.: 10

Bravo AF: 0.0163

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.000382

EpiControl AF: 0.000356

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	Hyperalphalipoproteinemia 1 (2)
-	-	1	CETP-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.73
CADD	Benign	1.5
DANN	Benign	0.42
PhyloP100		1.3
PromoterAI		0.00060	Neutral
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs5884; hg19: chr16-56995957;