8-142879686-C-T

Variant names:

• chr8-142879686-C-T
• rs4534
• NM_000497.4:c.128G>A

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 3P and 20B. PM1 PP2 BP4_Strong BP6_Very_Strong BA1

The NM_000497.4(CYP11B1):​c.128G>A​(p.Arg43Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0428 in 1,614,192 control chromosomes in the GnomAD database, including 6,762 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R43W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.048 (740 hom., cov: 31)
  • Exomes 𝑓: 0.042 (6022 hom.)
• Consequence: CYP11B1 NM_000497.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.228
• Publications: 34 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 -17 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 6 uncertain in NM_000497.4
• 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.
• BP4: Computational evidence support a benign effect (MetaRNN=1.160652E-4).
• BP6: Variant 8-142879686-C-T is Benign according to our data. Variant chr8-142879686-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 362170.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.429 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CYP11B1	NM_000497.4	MANE Select	c.128G>A	p.Arg43Gln	missense	Exon 1 of 9	NP_000488.3
	CYP11B1	NM_001026213.1		c.128G>A	p.Arg43Gln	missense	Exon 1 of 8	NP_001021384.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CYP11B1	ENST00000292427.10	TSL:1 MANE Select	c.128G>A	p.Arg43Gln	missense	Exon 1 of 9	ENSP00000292427.5
	CYP11B1	ENST00000377675.3	TSL:1	c.128G>A	p.Arg43Gln	missense	Exon 1 of 11	ENSP00000366903.3
	CYP11B1	ENST00000517471.5	TSL:1	c.128G>A	p.Arg43Gln	missense	Exon 1 of 8	ENSP00000428043.1

Frequencies

GnomAD3 genomes AF: 0.0477 AC: 7260 AN: 152194 Hom.: 736 Cov.: 31

Gnomad AFR AF: 0.0210

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.103

Gnomad ASJ AF: 0.0303

Gnomad EAS AF: 0.443

Gnomad SAS AF: 0.157

Gnomad FIN AF: 0.0262

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.0186

Gnomad OTH AF: 0.0501

GnomAD2 exomes AF: 0.0845 AC: 21242 AN: 251402 AF XY: 0.0825

Gnomad AFR exome AF: 0.0204

Gnomad AMR exome AF: 0.139

Gnomad ASJ exome AF: 0.0262

Gnomad EAS exome AF: 0.456

Gnomad FIN exome AF: 0.0274

Gnomad NFE exome AF: 0.0181

Gnomad OTH exome AF: 0.0567

GnomAD4 exome AF: 0.0422 AC: 61749 AN: 1461880 Hom.: 6022 Cov.: 35 AF XY: 0.0448 AC XY: 32556 AN XY: 727240

African (AFR) AF: 0.0204 AC: 682 AN: 33480

American (AMR) AF: 0.133 AC: 5941 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0250 AC: 653 AN: 26136

East Asian (EAS) AF: 0.448 AC: 17791 AN: 39700

South Asian (SAS) AF: 0.144 AC: 12425 AN: 86258

European-Finnish (FIN) AF: 0.0272 AC: 1450 AN: 53406

Middle Eastern (MID) AF: 0.0399 AC: 230 AN: 5768

European-Non Finnish (NFE) AF: 0.0173 AC: 19232 AN: 1112012

Other (OTH) AF: 0.0554 AC: 3345 AN: 60396

GnomAD4 genome AF: 0.0478 AC: 7274 AN: 152312 Hom.: 740 Cov.: 31 AF XY: 0.0539 AC XY: 4013 AN XY: 74478

African (AFR) AF: 0.0210 AC: 872 AN: 41574

American (AMR) AF: 0.104 AC: 1585 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.0303 AC: 105 AN: 3470

East Asian (EAS) AF: 0.444 AC: 2294 AN: 5164

South Asian (SAS) AF: 0.157 AC: 759 AN: 4828

European-Finnish (FIN) AF: 0.0262 AC: 278 AN: 10622

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

European-Non Finnish (NFE) AF: 0.0186 AC: 1267 AN: 68032

Other (OTH) AF: 0.0515 AC: 109 AN: 2116

Alfa AF: 0.0364 Hom.: 357

Bravo AF: 0.0507

TwinsUK AF: 0.0143 AC: 53

ALSPAC AF: 0.0197 AC: 76

ESP6500AA AF: 0.0232 AC: 102

ESP6500EA AF: 0.0197 AC: 169

ExAC AF: 0.0803 AC: 9754

Asia WGS AF: 0.262 AC: 909 AN: 3478

EpiCase AF: 0.0142

EpiControl AF: 0.0158

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.066
BayesDel_addAF	Benign	-0.73	T
BayesDel_noAF	Benign	-0.68
CADD	Benign	0.022
DANN	Benign	0.69
DEOGEN2	Benign	0.13	T
Eigen	Benign	-1.7
Eigen_PC	Benign	-1.8
FATHMM_MKL	Benign	0.0013	N
LIST_S2	Benign	0.18	T
MetaRNN	Benign	0.00012	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.83	N
PhyloP100		-0.23
PrimateAI	Benign	0.44	T
PROVEAN	Benign	1.2	N
REVEL	Benign	0.14
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.026
MPC		0.097
ClinPred		0.00082	T
GERP RS		-4.5
PromoterAI		0.010	Neutral
Varity_R		0.056
gMVP		0.21
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: rs4534; hg19: chr8-143961102; COSMIC: COSV52824896; COSMIC: COSV52824896;