chr8-142917752-C-G

Variant names:

• chr8-142917752-C-G
• rs6441
• NM_000498.3:c.89G>C

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_000498.3(CYP11B2):​c.89G>C​(p.Arg30Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,838 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R30Q) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: CYP11B2 NM_000498.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.288
• Publications: 10 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.06727874).

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.89G>C	p.Arg30Pro	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.89G>C	p.Arg30Pro	missense	Exon 1 of 9	ENSP00000325822.2	P19099
	CYP11B2	ENST00000945895.1		c.89G>C	p.Arg30Pro	missense	Exon 1 of 9	ENSP00000615954.1
	CYP11B2	ENST00000945896.1		c.89G>C	p.Arg30Pro	missense	Exon 1 of 9	ENSP00000615955.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461838 Hom.: 0 Cov.: 34 AF XY: 0.00000138 AC XY: 1 AN XY: 727222

African (AFR) AF: 0.0000299 AC: 1 AN: 33480

American (AMR) AF: 0.00 AC: 0 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: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53366

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1112012

Other (OTH) AF: 0.0000331 AC: 2 AN: 60396

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 1

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.068
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	0.064
DANN	Benign	0.46
DEOGEN2	Benign	0.12	T
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.0015	N
LIST_S2	Benign	0.31	T
M_CAP	Benign	0.062	D
MetaRNN	Benign	0.067	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.81	N
PhyloP100		-0.29
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-0.56	N
REVEL	Benign	0.17
Sift	Benign	0.28	T
Sift4G	Benign	0.30	T
Polyphen		0.0	B
Vest4		0.066
MutPred		0.42		Gain of loop (P = 0.0013)
MVP		0.37
MPC		0.33
ClinPred		0.082	T
GERP RS		-1.8
PromoterAI		-0.011	Neutral
Varity_R		0.10
gMVP		0.50
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: rs6441; hg19: chr8-143999168;