NM_000497.4:c.1343G>C

Variant names:

• chr8-142875012-C-G
• rs28934586
• NM_000497.4:c.1343G>C

Variant summary

Our verdict is Pathogenic. The variant received 19 ACMG points: 19P and 0B. PM1 PM2 PM5 PP2 PP3_Strong PP5_Very_Strong

The NM_000497.4(CYP11B1):​c.1343G>C​(p.Arg448Pro) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R448C) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: CYP11B1 NM_000497.4 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 6.64
• Publications: 34 publications found

Genes affected

CYP11B1 (HGNC:2591): (cytochrome P450 family 11 subfamily B member 1) 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 and is involved in the conversion of progesterone to cortisol in the adrenal cortex. Mutations in this gene cause congenital adrenal hyperplasia due to 11-beta-hydroxylase deficiency. Transcript variants encoding different isoforms have been noted for this gene. [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: Pathogenic. The variant received 19 ACMG points.

• PM1: In a hotspot region, there are 8 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 uncertain in NM_000497.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr8-142875013-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 1459491.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 45 curated pathogenic missense variants (we use a threshold of 10). The gene has 9 curated benign missense variants. Gene score misZ: -1.5619 (below the threshold of 3.09). Trascript score misZ: -0.26962 (below the threshold of 3.09). GenCC associations: The gene is linked to glucocorticoid-remediable aldosteronism, congenital adrenal hyperplasia due to 11-beta-hydroxylase deficiency.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.99
• PP5: Variant 8-142875012-C-G is Pathogenic according to our data. Variant chr8-142875012-C-G is described in ClinVar as Pathogenic. ClinVar VariationId is 1030831.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000497.4. 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
	CYP11B1	NM_000497.4	MANE Select	c.1343G>C	p.Arg448Pro	missense	Exon 8 of 9	NP_000488.3
	CYP11B1	NM_001026213.1		c.1200+222G>C		intron	N/A	NP_001021384.1	P15538-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CYP11B1	ENST00000292427.10	TSL:1 MANE Select	c.1343G>C	p.Arg448Pro	missense	Exon 8 of 9	ENSP00000292427.5	P15538-1
	CYP11B1	ENST00000377675.3	TSL:1	c.1556G>C	p.Arg519Pro	missense	Exon 10 of 11	ENSP00000366903.3	Q4VAR0
	CYP11B1	ENST00000519285.5	TSL:1	c.377G>C	p.Arg126Pro	missense	Exon 3 of 4	ENSP00000430144.1	H0YBR4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
1	-	-	Deficiency of steroid 11-beta-monooxygenase (1)
1	-	-	Glucocorticoid-remediable aldosteronism (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.87
BayesDel_addAF	Pathogenic	0.46	D
BayesDel_noAF	Pathogenic	0.43
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Benign	0.29	T
Eigen	Pathogenic	0.72
Eigen_PC	Uncertain	0.57
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.96	D
M_CAP	Pathogenic	0.58	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	0.84	D
MutationAssessor	Pathogenic	3.2	M
PhyloP100		6.6
PrimateAI	Uncertain	0.72	T
PROVEAN	Pathogenic	-6.4	D
REVEL	Pathogenic	0.90
Sift	Uncertain	0.010	D
Sift4G	Uncertain	0.024	D
Polyphen		1.0	D
Vest4		0.90
MutPred		0.95		Loss of MoRF binding (P = 0.0482)
MVP		0.94
MPC		0.56
ClinPred		1.0	D
GERP RS		4.2
Varity_R		1.0
gMVP		0.98
Mutation Taster		=6/94	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs28934586; hg19: chr8-143956428;