chr8-142877856-T-C

Variant names:

• chr8-142877856-T-C
• rs9657021
• NM_000497.4:c.396-634A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000497.4(CYP11B1):​c.396-634A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.05 in 1,583,204 control chromosomes in the GnomAD database, including 6,760 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. There are indicators that this mutation may affect the branch point..

• Frequency:
  • Genomes: 𝑓 0.13 (3030 hom., cov: 34)
  • Exomes 𝑓: 0.042 (3730 hom.)
• Consequence: CYP11B1 NM_000497.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.778
• Publications: 3 publications found

Genes affected

CYP11B1 (HGNC:2591): (cytochrome P450 family 11 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 protein localizes to the mitochondrial inner membrane and is involved in the conversion of progesterone to cortisol in the adrenal cortex. Mutations in this gene cause congenital adrenal hyperplasia due to 11-beta-hydroxylase deficiency. Transcript variants encoding different isoforms have been noted for this gene. [provided by RefSeq, Jul 2008]

GML (HGNC:4375): (glycosylphosphatidylinositol anchored molecule like) Predicted to be involved in DNA damage response, signal transduction by p53 class mediator resulting in cell cycle arrest; apoptotic process; and negative regulation of cell population proliferation. Predicted to be extrinsic component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.364 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000497.4. 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
	CYP11B1	NM_000497.4	MANE Select	c.396-634A>G		intron	N/A	NP_000488.3
	CYP11B1	NM_001026213.1		c.396-634A>G		intron	N/A	NP_001021384.1	P15538-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CYP11B1	ENST00000292427.10	TSL:1 MANE Select	c.396-634A>G		intron	N/A	ENSP00000292427.5	P15538-1
	CYP11B1	ENST00000377675.3	TSL:1	c.531-22A>G		intron	N/A	ENSP00000366903.3	Q4VAR0
	CYP11B1	ENST00000517471.5	TSL:1	c.396-634A>G		intron	N/A	ENSP00000428043.1	P15538-2

Frequencies

GnomAD3 genomes AF: 0.129 AC: 19641 AN: 152088 Hom.: 3018 Cov.: 34

Gnomad AFR AF: 0.369

Gnomad AMI AF: 0.00987

Gnomad AMR AF: 0.0625

Gnomad ASJ AF: 0.0406

Gnomad EAS AF: 0.0787

Gnomad SAS AF: 0.0820

Gnomad FIN AF: 0.0375

Gnomad MID AF: 0.0823

Gnomad NFE AF: 0.0262

Gnomad OTH AF: 0.127

GnomAD2 exomes AF: 0.0663 AC: 14592 AN: 220204 AF XY: 0.0615

Gnomad AFR exome AF: 0.384

Gnomad AMR exome AF: 0.0512

Gnomad ASJ exome AF: 0.0506

Gnomad EAS exome AF: 0.0794

Gnomad FIN exome AF: 0.0407

Gnomad NFE exome AF: 0.0278

Gnomad OTH exome AF: 0.0521

GnomAD4 exome AF: 0.0416 AC: 59527 AN: 1430998 Hom.: 3730 Cov.: 31 AF XY: 0.0418 AC XY: 29761 AN XY: 712720

African (AFR) AF: 0.390 AC: 12826 AN: 32884

American (AMR) AF: 0.0523 AC: 2163 AN: 41382

Ashkenazi Jewish (ASJ) AF: 0.0519 AC: 1338 AN: 25770

East Asian (EAS) AF: 0.0693 AC: 2742 AN: 39552

South Asian (SAS) AF: 0.0751 AC: 6335 AN: 84400

European-Finnish (FIN) AF: 0.0386 AC: 1464 AN: 37968

Middle Eastern (MID) AF: 0.103 AC: 587 AN: 5714

European-Non Finnish (NFE) AF: 0.0258 AC: 28437 AN: 1103668

Other (OTH) AF: 0.0609 AC: 3635 AN: 59660

GnomAD4 genome AF: 0.129 AC: 19694 AN: 152206 Hom.: 3030 Cov.: 34 AF XY: 0.127 AC XY: 9477 AN XY: 74430

African (AFR) AF: 0.369 AC: 15315 AN: 41502

American (AMR) AF: 0.0625 AC: 956 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.0406 AC: 141 AN: 3470

East Asian (EAS) AF: 0.0789 AC: 408 AN: 5174

South Asian (SAS) AF: 0.0822 AC: 397 AN: 4828

European-Finnish (FIN) AF: 0.0375 AC: 398 AN: 10612

Middle Eastern (MID) AF: 0.0884 AC: 26 AN: 294

European-Non Finnish (NFE) AF: 0.0262 AC: 1780 AN: 67998

Other (OTH) AF: 0.125 AC: 264 AN: 2114

Alfa AF: 0.0555 Hom.: 1016

Bravo AF: 0.143

Asia WGS AF: 0.100 AC: 348 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	6.1
DANN	Benign	0.74
PhyloP100		-0.78
La Branchor		0.57
Mutation Taster		=100/0	polymorphism (auto)

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: rs9657021; hg19: chr8-143959272; COSMIC: COSV52825440; COSMIC: COSV52825440;