8-142879042-C-T

Variant names:

• chr8-142879042-C-T
• rs377423817
• NM_000497.4:c.385G>A

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 1P and 0B. PP2

The NM_000497.4(CYP11B1):​c.385G>A​(p.Val129Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000253 in 1,461,874 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V129L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000025 (0 hom.)
• Consequence: CYP11B1 NM_000497.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: -0.0150
• 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: Uncertain_significance. The variant received 1 ACMG points.

• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 45 curated pathogenic missense variants (we use a threshold of 10). The gene has 9 curated benign missense variants. Gene score misZ: -1.5619 (below the threshold of 3.09). Trascript score misZ: -0.26962 (below the threshold of 3.09). GenCC associations: The gene is linked to glucocorticoid-remediable aldosteronism, congenital adrenal hyperplasia due to 11-beta-hydroxylase deficiency.

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.385G>A	p.Val129Met	missense	Exon 2 of 9	NP_000488.3
	CYP11B1	NM_001026213.1		c.385G>A	p.Val129Met	missense	Exon 2 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.385G>A	p.Val129Met	missense	Exon 2 of 9	ENSP00000292427.5	P15538-1
	CYP11B1	ENST00000377675.3	TSL:1	c.520G>A	p.Val174Met	missense	Exon 3 of 11	ENSP00000366903.3	Q4VAR0
	CYP11B1	ENST00000517471.5	TSL:1	c.385G>A	p.Val129Met	missense	Exon 2 of 8	ENSP00000428043.1	P15538-2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000159 AC: 4 AN: 251346 AF XY: 0.0000147

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000264

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000253 AC: 37 AN: 1461874 Hom.: 0 Cov.: 32 AF XY: 0.0000220 AC XY: 16 AN XY: 727236

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44722

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

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.0000580 AC: 5 AN: 86256

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53410

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.0000252 AC: 28 AN: 1112006

Other (OTH) AF: 0.0000331 AC: 2 AN: 60396

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Deficiency of steroid 11-beta-monooxygenase (1)
-	1	-	Deficiency of steroid 11-beta-monooxygenase;C3838731:Glucocorticoid-remediable aldosteronism (1)
-	1	-	Glucocorticoid-remediable aldosteronism (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.36
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	0.030
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.69	D
Eigen	Uncertain	0.27
Eigen_PC	Benign	0.071
FATHMM_MKL	Benign	0.051	N
LIST_S2	Uncertain	0.91	D
M_CAP	Pathogenic	0.62	D
MetaRNN	Uncertain	0.72	D
MetaSVM	Uncertain	-0.020	T
MutationAssessor	Pathogenic	3.1	M
PhyloP100		-0.015
PrimateAI	Uncertain	0.64	T
PROVEAN	Uncertain	-2.4	N
REVEL	Uncertain	0.52
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0020	D
Polyphen		1.0	D
Vest4		0.44
MVP		0.77
MPC		0.46
ClinPred		0.87	D
GERP RS		1.4
Varity_R		0.81
gMVP		0.49
Mutation Taster		=12/88	disease causing

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: rs377423817; hg19: chr8-143960458;