8-142915137-G-C

Variant names:

• chr8-142915137-G-C
• rs4546
• NM_000498.3:c.504C>G

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_000498.3(CYP11B2):​c.504C>G​(p.Phe168Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. F168F) has been classified as Benign.

• Frequency: Genomes: not found (cov: 31)
• Consequence: CYP11B2 NM_000498.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.58
• Publications: 20 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: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.746

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.504C>G	p.Phe168Leu	missense	Exon 3 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.504C>G	p.Phe168Leu	missense	Exon 3 of 9	ENSP00000325822.2
	GML	ENST00000522728.5	TSL:3	c.264+1092G>C		intron	N/A	ENSP00000430799.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 49

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.93
BayesDel_addAF	Benign	-0.068	T
BayesDel_noAF	Benign	-0.34
CADD	Benign	21
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.56	D
Eigen	Benign	-0.32
Eigen_PC	Benign	-0.47
FATHMM_MKL	Benign	0.64	D
LIST_S2	Uncertain	0.87	D
M_CAP	Uncertain	0.18	D
MetaRNN	Pathogenic	0.75	D
MetaSVM	Benign	-0.82	T
MutationAssessor	Benign	1.9	M
PhyloP100		1.6
PrimateAI	Uncertain	0.66	T
PROVEAN	Pathogenic	-5.8	D
REVEL	Benign	0.29
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.85	P
Vest4		0.42
MutPred		0.73		Gain of disorder (P = 0.12)
MVP		0.62
MPC		0.55
ClinPred		0.98	D
GERP RS		1.6
Varity_R		0.93
gMVP		0.78
Mutation Taster		=85/15	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: rs4546; hg19: chr8-143996553;