8-142913390-A-T

Variant names:

• chr8-142913390-A-T
• rs4544
• NM_000498.3:c.1016T>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

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. 15/21 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. I339V) 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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.599
• Publications: 30 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=0.020480663).
• BP6: Variant 8-142913390-A-T is Benign according to our data. Variant chr8-142913390-A-T is described in ClinVar as Benign. ClinVar VariationId 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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 31 AR gene

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CYP11B2	NM_000498.3	MANE Select	c.1016T>A	p.Ile339Asn	missense	Exon 6 of 9	NP_000489.3	P19099

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CYP11B2	ENST00000323110.2	TSL:1 MANE Select	c.1016T>A	p.Ile339Asn	missense	Exon 6 of 9	ENSP00000325822.2	P19099
	CYP11B2	ENST00000945895.1		c.1016T>A	p.Ile339Asn	missense	Exon 6 of 9	ENSP00000615954.1
	CYP11B2	ENST00000945896.1		c.1016T>A	p.Ile339Asn	missense	Exon 6 of 9	ENSP00000615955.1

Frequencies

GnomAD3 genomes AF: 0.00101 AC: 153 AN: 151990 Hom.: 0 Cov.: 32

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

GnomAD2 exomes AF: 0.00303 AC: 759 AN: 250774 AF XY: 0.00415

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 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.: 31 Cov.: 37 AF XY: 0.00220 AC XY: 1598 AN XY: 727152

African (AFR) AF: 0.000209 AC: 7 AN: 33480

American (AMR) AF: 0.000827 AC: 37 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.000689 AC: 18 AN: 26136

East Asian (EAS) AF: 0.000378 AC: 15 AN: 39698

South Asian (SAS) AF: 0.0206 AC: 1774 AN: 86256

European-Finnish (FIN) AF: 0.0000188 AC: 1 AN: 53232

Middle Eastern (MID) AF: 0.00780 AC: 45 AN: 5768

European-Non Finnish (NFE) AF: 0.000313 AC: 348 AN: 1112000

Other (OTH) AF: 0.00179 AC: 108 AN: 60394

GnomAD4 genome AF: 0.00101 AC: 154 AN: 152108 Hom.: 0 Cov.: 32 AF XY: 0.00147 AC XY: 109 AN XY: 74368

African (AFR) AF: 0.0000724 AC: 3 AN: 41458

American (AMR) AF: 0.000719 AC: 11 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.000576 AC: 2 AN: 3470

East Asian (EAS) AF: 0.000194 AC: 1 AN: 5152

South Asian (SAS) AF: 0.0199 AC: 96 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.000530 AC: 36 AN: 67976

Other (OTH) AF: 0.000947 AC: 2 AN: 2112

Alfa AF: 0.0000186 Hom.: 3492

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000259 AC: 1

ExAC AF: 0.00346 AC: 420

EpiCase AF: 0.000872

EpiControl AF: 0.000771

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Corticosterone 18-monooxygenase deficiency (1)
-	-	1	Corticosterone methyloxidase type 2 deficiency (1)
-	-	1	Glucocorticoid-remediable aldosteronism (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.081
BayesDel_addAF	Benign	-0.51	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	21
DANN	Benign	0.94
DEOGEN2	Benign	0.088	T
Eigen	Benign	-0.97
Eigen_PC	Benign	-0.88
FATHMM_MKL	Benign	0.035	N
LIST_S2	Benign	0.33	T
MetaRNN	Benign	0.020	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	-0.34	N
PhyloP100		0.60
PrimateAI	Uncertain	0.66	T
PROVEAN	Benign	-0.080	N
REVEL	Benign	0.055
Sift	Benign	0.074	T
Sift4G	Benign	0.39	T
Polyphen		0.0	B
Vest4		0.17
MVP		0.39
MPC		0.40
ClinPred		0.0066	T
GERP RS		3.7
Varity_R		0.20
gMVP		0.78
Mutation Taster		=92/8	polymorphism

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: rs4544; hg19: chr8-143994806;