8-142912850-A-G

Variant names:

• chr8-142912850-A-G
• rs61757294
• NM_000498.3:c.1157T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000498.3(CYP11B2):​c.1157T>C​(p.Val386Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.107 in 1,597,830 control chromosomes in the GnomAD database, including 10,505 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar. Synonymous variant affecting the same amino acid position (i.e. V386V) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.088 (713 hom., cov: 32)
  • Exomes 𝑓: 0.11 (9792 hom.)
• Consequence: CYP11B2 NM_000498.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9 O:1
• Conservation: PhyloP100: 0.379
• Publications: 38 publications found

Genes affected

CYP11B2 (HGNC:2592): (cytochrome P450 family 11 subfamily B member 2) 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. The enzyme has steroid 18-hydroxylase activity to synthesize aldosterone and 18-oxocortisol as well as steroid 11 beta-hydroxylase activity. Mutations in this gene cause corticosterone methyl oxidase deficiency. [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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0076085925).
• BP6: Variant 8-142912850-A-G is Benign according to our data. Variant chr8-142912850-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 242772.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.117 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000498.3. 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
	CYP11B2	NM_000498.3	MANE Select	c.1157T>C	p.Val386Ala	missense	Exon 7 of 9	NP_000489.3

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CYP11B2	ENST00000323110.2	TSL:1 MANE Select	c.1157T>C	p.Val386Ala	missense	Exon 7 of 9	ENSP00000325822.2
	GML	ENST00000522728.5	TSL:3	c.182-1113A>G		intron	N/A	ENSP00000430799.1

Frequencies

GnomAD3 genomes AF: 0.0883 AC: 13358 AN: 151294 Hom.: 711 Cov.: 32

Gnomad AFR AF: 0.0410

Gnomad AMI AF: 0.0615

Gnomad AMR AF: 0.0790

Gnomad ASJ AF: 0.134

Gnomad EAS AF: 0.00290

Gnomad SAS AF: 0.108

Gnomad FIN AF: 0.0992

Gnomad MID AF: 0.170

Gnomad NFE AF: 0.120

Gnomad OTH AF: 0.103

GnomAD2 exomes AF: 0.0845 AC: 20671 AN: 244568 AF XY: 0.0885

Gnomad AFR exome AF: 0.0284

Gnomad AMR exome AF: 0.0546

Gnomad ASJ exome AF: 0.116

Gnomad EAS exome AF: 0.00125

Gnomad FIN exome AF: 0.0910

Gnomad NFE exome AF: 0.104

Gnomad OTH exome AF: 0.0984

GnomAD4 exome AF: 0.108 AC: 156905 AN: 1446418 Hom.: 9792 Cov.: 44 AF XY: 0.110 AC XY: 78858 AN XY: 719516

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

African (AFR) AF: 0.0360 AC: 1193 AN: 33154

American (AMR) AF: 0.0604 AC: 2681 AN: 44368

Ashkenazi Jewish (ASJ) AF: 0.129 AC: 3338 AN: 25954

East Asian (EAS) AF: 0.00101 AC: 40 AN: 39690

South Asian (SAS) AF: 0.123 AC: 10546 AN: 85692

European-Finnish (FIN) AF: 0.0955 AC: 5082 AN: 53220

Middle Eastern (MID) AF: 0.156 AC: 873 AN: 5606

European-Non Finnish (NFE) AF: 0.116 AC: 127187 AN: 1098876

Other (OTH) AF: 0.0997 AC: 5965 AN: 59858

⚠️ 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: 0.0883 AC: 13365 AN: 151412 Hom.: 713 Cov.: 32 AF XY: 0.0867 AC XY: 6415 AN XY: 73996

African (AFR) AF: 0.0410 AC: 1684 AN: 41056

American (AMR) AF: 0.0789 AC: 1201 AN: 15226

Ashkenazi Jewish (ASJ) AF: 0.134 AC: 465 AN: 3470

East Asian (EAS) AF: 0.00290 AC: 15 AN: 5168

South Asian (SAS) AF: 0.108 AC: 517 AN: 4782

European-Finnish (FIN) AF: 0.0992 AC: 1048 AN: 10568

Middle Eastern (MID) AF: 0.176 AC: 51 AN: 290

European-Non Finnish (NFE) AF: 0.120 AC: 8114 AN: 67848

Other (OTH) AF: 0.102 AC: 214 AN: 2094

Alfa AF: 0.0822 Hom.: 320

ESP6500AA AF: 0.0270 AC: 119

ESP6500EA AF: 0.0955 AC: 821

ExAC AF: 0.0887 AC: 10768

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Sep 06, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 20981092, 9703385, 27125267, 21237269, 1594605, 11174838, 22465514, 22995991, 10965212, 27884173, 7485152, 28190867, 16733366, 9814506, 30864636)

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Jan 28, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Corticosterone methyloxidase type 2 deficiency Benign:2 Other:1

GenomeConnect, ClinGen

Significance: not provided

Review Status: no classification provided

Collection Method: phenotyping only

Variant interpretted as Pathogenic and reported on 05-03-2012 by Lab or GTR ID 504843. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.

May 28, 2019

Mendelics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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.

Corticosterone 18-monooxygenase deficiency 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). 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.

Feb 15, 2020

Natera, Inc.

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Corticosterone 18-monooxygenase deficiency;C3463917:Corticosterone methyloxidase type 2 deficiency Benign:1

Jun 12, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Likely 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). 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 v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Benign	-0.62	T
BayesDel_noAF	Benign	-0.57
CADD	Benign	2.5
DANN	Benign	0.53
DEOGEN2	Benign	0.17	T
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.0058	N
LIST_S2	Benign	0.34	T
MetaRNN	Benign	0.0076	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.8	L
PhyloP100		0.38
PrimateAI	Uncertain	0.65	T
PROVEAN	Benign	-1.7	N
REVEL	Uncertain	0.34
Sift	Benign	0.21	T
Sift4G	Benign	0.47	T
Polyphen		0.0	B
Vest4		0.015
MPC		0.28
ClinPred		0.0095	T
GERP RS		-2.4
Varity_R		0.19
gMVP		0.89
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs61757294; hg19: chr8-143994266; COSMIC: COSV59994312;