rs151335623

Variant names:

• chr8-142875819-C-G
• rs151335623
• NM_000497.4:c.1014G>C

Your query was ambiguous. Multiple possible variants found:

• chr8-142875819-C-G
• chr8-142875819-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 5P and 1B. PM1 PM2 PP2 BP4

The NM_000497.4(CYP11B1):​c.1014G>C​(p.Gln338His) 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 1,461,842 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign 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. Q338Q) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: CYP11B1 NM_000497.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.107
• Publications: 0 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: Uncertain_significance. The variant received 4 ACMG points.

• PM1: In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 9 uncertain in NM_000497.4
• PM2: Very rare variant in population databases, with high coverage
• 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.
• BP4: Computational evidence support a benign effect (MetaRNN=0.31737608).

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.1014G>C	p.Gln338His	missense	Exon 6 of 9	NP_000488.3
	CYP11B1	NM_001026213.1		c.1014G>C	p.Gln338His	missense	Exon 6 of 8	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.1014G>C	p.Gln338His	missense	Exon 6 of 9	ENSP00000292427.5	P15538-1
	CYP11B1	ENST00000377675.3	TSL:1	c.1227G>C	p.Gln409His	missense	Exon 8 of 11	ENSP00000366903.3	Q4VAR0
	CYP11B1	ENST00000517471.5	TSL:1	c.1014G>C	p.Gln338His	missense	Exon 6 of 8	ENSP00000428043.1	P15538-2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461842 Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1 AN XY: 727234

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44720

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: 53382

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

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1112004

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	15
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.69	D
Eigen	Benign	-0.17
Eigen_PC	Benign	-0.17
FATHMM_MKL	Benign	0.33	N
LIST_S2	Benign	0.59	T
M_CAP	Uncertain	0.26	D
MetaRNN	Benign	0.32	T
MetaSVM	Benign	-0.47	T
MutationAssessor	Benign	1.9	L
PhyloP100		0.11
PrimateAI	Uncertain	0.71	T
PROVEAN	Uncertain	-2.9	D
REVEL	Benign	0.16
Sift	Benign	0.045	D
Sift4G	Benign	0.086	T
Polyphen		0.28	B
Vest4		0.13
MutPred		0.45		Gain of catalytic residue at L411 (P = 0.0651)
MVP		0.83
MPC		0.13
ClinPred		0.57	D
GERP RS		2.4
PromoterAI		-0.069	Neutral
Varity_R		0.40
gMVP		0.74
Mutation Taster		=35/65	disease causing

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: rs151335623; hg19: chr8-143957235;