8-142913390-A-T

Position:

chr8-142913390-A-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_000498.3(CYP11B2):c.1016T>A(p.Ile339Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00155 in 1,613,796 control chromosomes in the GnomAD database, including 31 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 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. I339T) has been classified as Benign.

Frequency

Genomes: 𝑓 0.0010 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0016 ( 31 hom. )

Consequence

CYP11B2
NM_000498.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 0.599

Variant links:

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]

CYP11B2 links:

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]

GML links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.020480663).

BP6

Variant 8-142913390-A-T is Benign according to our data. Variant chr8-142913390-A-T is described in ClinVar as [Benign]. Clinvar id is 362202.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00101 (154/152108) while in subpopulation SAS AF= 0.0199 (96/4820). AF 95% confidence interval is 0.0167. There are 0 homozygotes in gnomad4. There are 109 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAdExome4 at 31 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CYP11B2	NM_000498.3 linkuse as main transcript	c.1016T>A	p.Ile339Asn	missense_variant	6/9	ENST00000323110.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CYP11B2	ENST00000323110.2 linkuse as main transcript	c.1016T>A	p.Ile339Asn	missense_variant	6/9	1	NM_000498.3	P1
GML	ENST00000522728.5 linkuse as main transcript	c.182-573A>T		intron_variant		3

Frequencies

GnomAD3 genomes

AF:

0.00101

AC:

153

AN:

151990

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000726

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000720

Gnomad ASJ

AF:

0.000576

Gnomad EAS

AF:

0.000194

Gnomad SAS

AF:

0.0197

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.000530

Gnomad OTH

AF:

0.000957

GnomAD3 exomes

AF:

0.00303

AC:

759

AN:

250774

Hom.:

AF XY:

0.00415

AC XY:

563

AN XY:

135694

show subpopulations

Gnomad AFR exome

AF:

0.0000617

Gnomad AMR exome

AF:

0.000781

Gnomad ASJ exome

AF:

0.000894

Gnomad EAS exome

AF:

0.000708

Gnomad SAS exome

AF:

0.0209

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000504

Gnomad OTH exome

AF:

0.00196

GnomAD4 exome

AF:

0.00161

AC:

2353

AN:

1461688

Hom.:

Cov.:

AF XY:

0.00220

AC XY:

1598

AN XY:

727152

show subpopulations

Gnomad4 AFR exome

AF:

0.000209

Gnomad4 AMR exome

AF:

0.000827

Gnomad4 ASJ exome

AF:

0.000689

Gnomad4 EAS exome

AF:

0.000378

Gnomad4 SAS exome

AF:

0.0206

Gnomad4 FIN exome

AF:

0.0000188

Gnomad4 NFE exome

AF:

0.000313

Gnomad4 OTH exome

AF:

0.00179

GnomAD4 genome

AF:

0.00101

AC:

154

AN:

152108

Hom.:

Cov.:

AF XY:

0.00147

AC XY:

109

AN XY:

74368

show subpopulations

Gnomad4 AFR

AF:

0.0000724

Gnomad4 AMR

AF:

0.000719

Gnomad4 ASJ

AF:

0.000576

Gnomad4 EAS

AF:

0.000194

Gnomad4 SAS

AF:

0.0199

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000530

Gnomad4 OTH

AF:

0.000947

Alfa

AF:

0.0000378

Hom.:

453

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000259

AC:

ExAC

AF:

0.00346

AC:

420

EpiCase

AF:

0.000872

EpiControl

AF:

0.000771

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Corticosterone methyloxidase type 2 deficiency

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Corticosterone 18-monooxygenase deficiency

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Glucocorticoid-remediable aldosteronism

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.081

BayesDel_addAF

Benign

-0.51

BayesDel_noAF

Benign

-0.49

CADD

Benign

DANN

Benign

0.94

DEOGEN2

Benign

0.088

Eigen

Benign

-0.97

Eigen_PC

Benign

-0.88

FATHMM_MKL

Benign

0.035

LIST_S2

Benign

0.33

MetaRNN

Benign

0.020

MetaSVM

Benign

-0.99

MutationAssessor

Benign

-0.34

MutationTaster

Benign

1.0

PrimateAI

Uncertain

0.66

PROVEAN

Benign

-0.080

REVEL

Benign

0.055

Sift

Benign

0.074

Sift4G

Benign

0.39

Polyphen

0.0

Vest4

0.17

MVP

0.39

MPC

0.40

ClinPred

0.0066

GERP RS

3.7

Varity_R

0.20

gMVP

0.78

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over