rs6438

Variant names:

• chr8-142917756-C-T
• rs6438
• NM_000498.3:c.85G>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.85G>A​(p.Ala29Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00182 in 1,614,200 control chromosomes in the GnomAD database, including 52 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.010 (31 hom., cov: 33)
  • Exomes 𝑓: 0.00096 (21 hom.)
• Consequence: CYP11B2 NM_000498.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -2.85
• Publications: 9 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]

CYP11B2 Gene-Disease associations (from GenCC):

• familial hyperreninemic hypoaldosteronism type 2

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• corticosterone methyloxidase type 2 deficiency

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• corticosterone methyloxidase type 1 deficiency

  Inheritance: AR Classification: MODERATE Submitted by: Ambry Genetics
• familial hypoaldosteronism

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0023329556).
• BP6: Variant 8-142917756-C-T is Benign according to our data. Variant chr8-142917756-C-T is described in ClinVar as Benign. ClinVar VariationId is 716151.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.01 (1525/152382) while in subpopulation AFR AF = 0.0354 (1474/41598). AF 95% confidence interval is 0.0339. There are 31 homozygotes in GnomAd4. There are 726 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 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.85G>A	p.Ala29Thr	missense	Exon 1 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.85G>A	p.Ala29Thr	missense	Exon 1 of 9	ENSP00000325822.2	P19099
	CYP11B2	ENST00000945895.1		c.85G>A	p.Ala29Thr	missense	Exon 1 of 9	ENSP00000615954.1
	CYP11B2	ENST00000945896.1		c.85G>A	p.Ala29Thr	missense	Exon 1 of 9	ENSP00000615955.1

Frequencies

GnomAD3 genomes AF: 0.0100 AC: 1523 AN: 152262 Hom.: 31 Cov.: 33

Gnomad AFR AF: 0.0355

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00170

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000265

Gnomad OTH AF: 0.00335

GnomAD2 exomes AF: 0.00253 AC: 636 AN: 251216 AF XY: 0.00190

Gnomad AFR exome AF: 0.0362

Gnomad AMR exome AF: 0.000925

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000705

Gnomad OTH exome AF: 0.00114

GnomAD4 exome AF: 0.000963 AC: 1408 AN: 1461818 Hom.: 21 Cov.: 34 AF XY: 0.000787 AC XY: 572 AN XY: 727216

African (AFR) AF: 0.0351 AC: 1175 AN: 33480

American (AMR) AF: 0.00143 AC: 64 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000580 AC: 5 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53346

Middle Eastern (MID) AF: 0.00139 AC: 8 AN: 5768

European-Non Finnish (NFE) AF: 0.0000279 AC: 31 AN: 1112012

Other (OTH) AF: 0.00207 AC: 125 AN: 60396

GnomAD4 genome AF: 0.0100 AC: 1525 AN: 152382 Hom.: 31 Cov.: 33 AF XY: 0.00974 AC XY: 726 AN XY: 74518

African (AFR) AF: 0.0354 AC: 1474 AN: 41598

American (AMR) AF: 0.00170 AC: 26 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10628

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000265 AC: 18 AN: 68036

Other (OTH) AF: 0.00331 AC: 7 AN: 2114

Alfa AF: 0.00403 Hom.: 6

Bravo AF: 0.0111

ESP6500AA AF: 0.0350 AC: 154

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00329 AC: 399

Asia WGS AF: 0.00173 AC: 7 AN: 3478

EpiCase AF: 0.000218

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.075
BayesDel_addAF	Benign	-0.65	T
BayesDel_noAF	Benign	-0.68
CADD	Benign	0.34
DANN	Benign	0.59
DEOGEN2	Benign	0.13	T
Eigen	Benign	-2.1
Eigen_PC	Benign	-2.2
FATHMM_MKL	Benign	0.0049	N
LIST_S2	Benign	0.49	T
MetaRNN	Benign	0.0023	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	0.83	L
PhyloP100		-2.8
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-1.2	N
REVEL	Benign	0.15
Sift	Benign	0.58	T
Sift4G	Benign	0.26	T
Polyphen		0.0010	B
Vest4		0.049
MVP		0.38
MPC		0.22
ClinPred		0.016	T
GERP RS		-7.0
PromoterAI		-0.0013	Neutral
Varity_R		0.042
gMVP		0.34
Mutation Taster		=100/0	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: rs6438; hg19: chr8-143999172; COSMIC: COSV59997760; COSMIC: COSV59997760;