3-42875019-C-A

Position:

• chr3-42875019-C-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_004391.3(CYP8B1):​c.798G>T​(p.Gly266=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00472 in 1,613,794 control chromosomes in the GnomAD database, including 322 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.025 (169 hom., cov: 32)
  • Exomes 𝑓: 0.0026 (153 hom.)
• Consequence: CYP8B1 NM_004391.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -4.05

Genes affected

CYP8B1 (HGNC:2653): (cytochrome P450 family 8 subfamily B member 1) This gene encodes a member of the cytochrome P450 superfamily of enzymes. The cytochrome P450 proteins are monooxygenases which catalyze many reactions involved in drug metabolism and synthesis of cholesterol, steroids and other lipids. This endoplasmic reticulum membrane protein catalyzes the conversion of 7 alpha-hydroxy-4-cholesten-3-one into 7-alpha,12-alpha-dihydroxy-4-cholesten-3-one. The balance between these two steroids determines the relative amounts of cholic acid and chenodeoxycholic acid both of which are secreted in the bile and affect the solubility of cholesterol. This gene is unique among the cytochrome P450 genes in that it is intronless. [provided by RefSeq, Jul 2008]

(HGNC:):

ACKR2 (HGNC:1565): (atypical chemokine receptor 2) This gene encodes a beta chemokine receptor, which is predicted to be a seven transmembrane protein similar to G protein-coupled receptors. Chemokines and their receptor-mediated signal transduction are critical for the recruitment of effector immune cells to the inflammation site. This gene is expressed in a range of tissues and hemopoietic cells. The expression of this receptor in lymphatic endothelial cells and overexpression in vascular tumors suggested its function in chemokine-driven recirculation of leukocytes and possible chemokine effects on the development and growth of vascular tumors. This receptor appears to bind the majority of beta-chemokine family members; however, its specific function remains unknown. This gene is mapped to chromosome 3p21.3, a region that includes a cluster of chemokine receptor genes. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 3-42875019-C-A is Benign according to our data. Variant chr3-42875019-C-A is described in ClinVar as [Benign]. Clinvar id is 770520.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-4.05 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0841 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CYP8B1	NM_004391.3	c.798G>T	p.Gly266=	synonymous_variant	1/1	ENST00000316161.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CYP8B1	ENST00000316161.6	c.798G>T	p.Gly266=	synonymous_variant	1/1		NM_004391.3	P1

Frequencies

GnomAD3 genomes AF: 0.0252 AC: 3836 AN: 152116 Hom.: 168 Cov.: 32

Gnomad AFR AF: 0.0867

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0125

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000250

Gnomad OTH AF: 0.0181

GnomAD3 exomes AF: 0.00687 AC: 1712 AN: 249304 Hom.: 56 AF XY: 0.00499 AC XY: 674 AN XY: 135204

Gnomad AFR exome AF: 0.0926

Gnomad AMR exome AF: 0.00559

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000131

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000240

Gnomad OTH exome AF: 0.00491

GnomAD4 exome AF: 0.00258 AC: 3778 AN: 1461560 Hom.: 153 Cov.: 32 AF XY: 0.00219 AC XY: 1590 AN XY: 727082

Gnomad4 AFR exome AF: 0.0886

Gnomad4 AMR exome AF: 0.00613

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000151

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000130

Gnomad4 OTH exome AF: 0.00585

GnomAD4 genome AF: 0.0252 AC: 3836 AN: 152234 Hom.: 169 Cov.: 32 AF XY: 0.0242 AC XY: 1803 AN XY: 74414

Gnomad4 AFR AF: 0.0864

Gnomad4 AMR AF: 0.0125

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000250

Gnomad4 OTH AF: 0.0180

Alfa AF: 0.00502 Hom.: 60

Bravo AF: 0.0289

Asia WGS AF: 0.00346 AC: 13 AN: 3478

EpiCase AF: 0.000164

EpiControl AF: 0.000356

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 31, 2019	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	0.043
DANN	Benign	0.63

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

Other links and lift over

dbSNP: rs741817; hg19: chr3-42916511;