rs4534

chr8-142879686-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. 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. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• 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:5
• Conservation: PhyloP100: -0.228

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

Verdict is Benign. Variant got -20 ACMG points.

• 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 [Likely_benign]. Clinvar id 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CYP11B1	NM_000497.4	c.128G>A	p.Arg43Gln	missense_variant	1/9	ENST00000292427.10
CYP11B1	NM_001026213.1	c.128G>A	p.Arg43Gln	missense_variant	1/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CYP11B1	ENST00000292427.10	c.128G>A	p.Arg43Gln	missense_variant	1/9	1	NM_000497.4	P1

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

GnomAD3 exomes AF: 0.0845 AC: 21242 AN: 251402 Hom.: 2690 AF XY: 0.0825 AC XY: 11216 AN XY: 135890

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 SAS exome AF: 0.145

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

Gnomad4 AFR exome AF: 0.0204

Gnomad4 AMR exome AF: 0.133

Gnomad4 ASJ exome AF: 0.0250

Gnomad4 EAS exome AF: 0.448

Gnomad4 SAS exome AF: 0.144

Gnomad4 FIN exome AF: 0.0272

Gnomad4 NFE exome AF: 0.0173

Gnomad4 OTH exome AF: 0.0554

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

Gnomad4 AFR AF: 0.0210

Gnomad4 AMR AF: 0.104

Gnomad4 ASJ AF: 0.0303

Gnomad4 EAS AF: 0.444

Gnomad4 SAS AF: 0.157

Gnomad4 FIN AF: 0.0262

Gnomad4 NFE AF: 0.0186

Gnomad4 OTH AF: 0.0515

Alfa AF: 0.0228 Hom.: 53

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

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Deficiency of steroid 11-beta-monooxygenase Benign:2

Benign, criteria provided, single submitter	clinical testing	Department of Human Genetics, Laborarztpraxis Dres. Walther, Weindel und Kollegen	Apr 17, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign. -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Dec 10, 2021

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Glucocorticoid-remediable aldosteronism Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -

Computational scores

Source: dbNSFP v4.3

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;T;T
MetaRNN	Benign	0.00012	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.83	N;N;.
MutationTaster	Benign	1.0	P;P;P
PrimateAI	Benign	0.44	T
PROVEAN	Benign	1.2	N;N;N
REVEL	Benign	0.14
Sift	Benign	1.0	T;T;T
Sift4G	Benign	1.0	T;T;T
Polyphen		0.0	B;.;B
Vest4		0.026
MPC		0.097
ClinPred		0.00082	T
GERP RS		-4.5
Varity_R		0.056
gMVP		0.21

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: rs4534; hg19: chr8-143961102; COSMIC: COSV52824896; COSMIC: COSV52824896;