chr8-142875277-G-A

Variant names:

• chr8-142875277-G-A
• rs4541
• NM_000497.4:c.1157C>T

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.1157C>T​(p.Ala386Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0409 in 1,603,440 control chromosomes in the GnomAD database, including 6,424 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A386E) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.054 (723 hom., cov: 33)
  • Exomes 𝑓: 0.040 (5701 hom.)
• Consequence: CYP11B1 NM_000497.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.420
• Publications: 26 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 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 1 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=0.0053716004).
• BP6: Variant 8-142875277-G-A is Benign according to our data. Variant chr8-142875277-G-A is described in ClinVar as Benign. ClinVar VariationId is 362149.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.415 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CYP11B1	NM_000497.4	c.1157C>T	p.Ala386Val	missense_variant	Exon 7 of 9	ENST00000292427.10	NP_000488.3
CYP11B1	NM_001026213.1	c.1157C>T	p.Ala386Val	missense_variant	Exon 7 of 8		NP_001021384.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CYP11B1	ENST00000292427.10	c.1157C>T	p.Ala386Val	missense_variant	Exon 7 of 9	1	NM_000497.4	ENSP00000292427.5

Frequencies

GnomAD3 genomes AF: 0.0537 AC: 8110 AN: 151134 Hom.: 719 Cov.: 33

Gnomad AFR AF: 0.0444

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.105

Gnomad ASJ AF: 0.0309

Gnomad EAS AF: 0.429

Gnomad SAS AF: 0.155

Gnomad FIN AF: 0.0261

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.0188

Gnomad OTH AF: 0.0582

GnomAD2 exomes AF: 0.0784 AC: 19408 AN: 247626 AF XY: 0.0764

Gnomad AFR exome AF: 0.0418

Gnomad AMR exome AF: 0.131

Gnomad ASJ exome AF: 0.0238

Gnomad EAS exome AF: 0.425

Gnomad FIN exome AF: 0.0250

Gnomad NFE exome AF: 0.0159

Gnomad OTH exome AF: 0.0547

GnomAD4 exome AF: 0.0396 AC: 57472 AN: 1452188 Hom.: 5701 Cov.: 35 AF XY: 0.0421 AC XY: 30458 AN XY: 722634

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0395 AC: 1309 AN: 33178

American (AMR) AF: 0.128 AC: 5660 AN: 44092

Ashkenazi Jewish (ASJ) AF: 0.0237 AC: 618 AN: 26064

East Asian (EAS) AF: 0.432 AC: 16771 AN: 38820

South Asian (SAS) AF: 0.138 AC: 11775 AN: 85138

European-Finnish (FIN) AF: 0.0264 AC: 1407 AN: 53312

Middle Eastern (MID) AF: 0.0347 AC: 189 AN: 5452

European-Non Finnish (NFE) AF: 0.0151 AC: 16653 AN: 1106394

Other (OTH) AF: 0.0517 AC: 3090 AN: 59738

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0537 AC: 8121 AN: 151252 Hom.: 723 Cov.: 33 AF XY: 0.0593 AC XY: 4388 AN XY: 73966

African (AFR) AF: 0.0443 AC: 1806 AN: 40800

American (AMR) AF: 0.105 AC: 1605 AN: 15248

Ashkenazi Jewish (ASJ) AF: 0.0309 AC: 107 AN: 3468

East Asian (EAS) AF: 0.430 AC: 2172 AN: 5054

South Asian (SAS) AF: 0.155 AC: 743 AN: 4800

European-Finnish (FIN) AF: 0.0261 AC: 277 AN: 10612

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

European-Non Finnish (NFE) AF: 0.0188 AC: 1281 AN: 67964

Other (OTH) AF: 0.0595 AC: 125 AN: 2100

Alfa AF: 0.0172 Hom.: 13

Bravo AF: 0.0588

TwinsUK AF: 0.0146 AC: 54

ALSPAC AF: 0.0202 AC: 78

ESP6500AA AF: 0.0390 AC: 172

ESP6500EA AF: 0.0170 AC: 146

ExAC AF: 0.0765 AC: 9291

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Deficiency of steroid 11-beta-monooxygenase Benign:2

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Apr 20, 2020

Department of Human Genetics, Laborarztpraxis Dres. Walther, Weindel und Kollegen

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Glucocorticoid-remediable aldosteronism Benign:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.056
BayesDel_addAF	Benign	-0.66	T
BayesDel_noAF	Benign	-0.58
CADD	Benign	8.8
DANN	Benign	0.75
DEOGEN2	Benign	0.0083	T;T;.;.
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.00087	N
LIST_S2	Benign	0.13	T;T;T;T
MetaRNN	Benign	0.0054	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-2.1	.;N;N;.
PhyloP100		0.42
PrimateAI	Uncertain	0.62	T
PROVEAN	Benign	2.0	N;N;N;N
REVEL	Benign	0.13
Sift	Benign	1.0	T;T;T;T
Sift4G	Benign	1.0	T;T;T;T
Polyphen		0.0	.;B;.;B
Vest4		0.043, 0.049
MPC		0.084
ClinPred		0.0014	T
GERP RS		1.9
Varity_R		0.070
gMVP		0.83
Mutation Taster		=86/14	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs4541; hg19: chr8-143956693; COSMIC: COSV52830014;