rs866430018

Variant names:

• chr8-142876741-C-T
• rs866430018
• NM_000497.4:c.740G>A

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PVS1 PP5_Very_Strong

The NM_000497.4(CYP11B1):​c.740G>A​(p.Trp247*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000123 in 1,461,716 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000012 (0 hom.)
• Consequence: CYP11B1 NM_000497.4 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 0.271
• 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: Pathogenic. The variant received 16 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant 8-142876741-C-T is Pathogenic according to our data. Variant chr8-142876741-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 554358.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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.740G>A	p.Trp247*	stop_gained	Exon 4 of 9	NP_000488.3
	CYP11B1	NM_001026213.1		c.740G>A	p.Trp247*	stop_gained	Exon 4 of 8	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.740G>A	p.Trp247*	stop_gained	Exon 4 of 9	ENSP00000292427.5	P15538-1
	CYP11B1	ENST00000377675.3	TSL:1	c.953G>A	p.Trp318*	stop_gained	Exon 6 of 11	ENSP00000366903.3	Q4VAR0
	CYP11B1	ENST00000517471.5	TSL:1	c.740G>A	p.Trp247*	stop_gained	Exon 4 of 8	ENSP00000428043.1	P15538-2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.0000123 AC: 18 AN: 1461716 Hom.: 0 Cov.: 86 AF XY: 0.0000165 AC XY: 12 AN XY: 727134

African (AFR) AF: 0.00 AC: 0 AN: 33468

American (AMR) AF: 0.00 AC: 0 AN: 44704

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.00 AC: 0 AN: 86202

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53410

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.0000162 AC: 18 AN: 1111950

Other (OTH) AF: 0.00 AC: 0 AN: 60388

GnomAD4 genome Cov.: 33

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
2	-	-	Deficiency of steroid 11-beta-monooxygenase (2)
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.65	D
BayesDel_noAF	Pathogenic	0.29
CADD	Pathogenic	38
DANN	Uncertain	0.99
Eigen	Uncertain	0.30
Eigen_PC	Benign	-0.0069
FATHMM_MKL	Benign	0.014	N
PhyloP100		0.27
Vest4		0.71
GERP RS		2.7
Mutation Taster		=3/197	disease causing (ClinVar)

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: rs866430018; hg19: chr8-143958157;