NM_000497.4:c.595+12G>A

Variant names:

• chr8-142877011-C-T
• rs6387
• NM_000497.4:c.595+12G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000497.4(CYP11B1):​c.595+12G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.546 in 1,612,492 control chromosomes in the GnomAD database, including 244,449 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.51 (20741 hom., cov: 31)
  • Exomes 𝑓: 0.55 (223708 hom.)
• Consequence: CYP11B1 NM_000497.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -3.01
• Publications: 13 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 8-142877011-C-T is Benign according to our data. Variant chr8-142877011-C-T is described in ClinVar as Benign. ClinVar VariationId is 362164.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.747 is higher than 0.05.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CYP11B1	NM_000497.4	MANE Select	c.595+12G>A		intron	N/A	NP_000488.3
	CYP11B1	NM_001026213.1		c.595+12G>A		intron	N/A	NP_001021384.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CYP11B1	ENST00000292427.10	TSL:1 MANE Select	c.595+12G>A		intron	N/A	ENSP00000292427.5
	CYP11B1	ENST00000377675.3	TSL:1	c.808+12G>A		intron	N/A	ENSP00000366903.3
	CYP11B1	ENST00000517471.5	TSL:1	c.595+12G>A		intron	N/A	ENSP00000428043.1

Frequencies

GnomAD3 genomes AF: 0.513 AC: 77902 AN: 151806 Hom.: 20731 Cov.: 31

Gnomad AFR AF: 0.368

Gnomad AMI AF: 0.549

Gnomad AMR AF: 0.586

Gnomad ASJ AF: 0.607

Gnomad EAS AF: 0.768

Gnomad SAS AF: 0.656

Gnomad FIN AF: 0.575

Gnomad MID AF: 0.579

Gnomad NFE AF: 0.540

Gnomad OTH AF: 0.529

GnomAD2 exomes AF: 0.576 AC: 143035 AN: 248318 AF XY: 0.582

Gnomad AFR exome AF: 0.363

Gnomad AMR exome AF: 0.609

Gnomad ASJ exome AF: 0.597

Gnomad EAS exome AF: 0.764

Gnomad FIN exome AF: 0.588

Gnomad NFE exome AF: 0.540

Gnomad OTH exome AF: 0.564

GnomAD4 exome AF: 0.550 AC: 802989 AN: 1460568 Hom.: 223708 Cov.: 64 AF XY: 0.554 AC XY: 402324 AN XY: 726488

African (AFR) AF: 0.360 AC: 12067 AN: 33474

American (AMR) AF: 0.604 AC: 26850 AN: 44462

Ashkenazi Jewish (ASJ) AF: 0.596 AC: 15564 AN: 26112

East Asian (EAS) AF: 0.771 AC: 30570 AN: 39662

South Asian (SAS) AF: 0.664 AC: 57177 AN: 86124

European-Finnish (FIN) AF: 0.586 AC: 31259 AN: 53356

Middle Eastern (MID) AF: 0.595 AC: 3426 AN: 5756

European-Non Finnish (NFE) AF: 0.533 AC: 592496 AN: 1111290

Other (OTH) AF: 0.557 AC: 33580 AN: 60332

GnomAD4 genome AF: 0.513 AC: 77941 AN: 151924 Hom.: 20741 Cov.: 31 AF XY: 0.522 AC XY: 38762 AN XY: 74248

African (AFR) AF: 0.368 AC: 15256 AN: 41434

American (AMR) AF: 0.586 AC: 8951 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.607 AC: 2105 AN: 3470

East Asian (EAS) AF: 0.767 AC: 3934 AN: 5130

South Asian (SAS) AF: 0.657 AC: 3157 AN: 4802

European-Finnish (FIN) AF: 0.575 AC: 6078 AN: 10564

Middle Eastern (MID) AF: 0.582 AC: 171 AN: 294

European-Non Finnish (NFE) AF: 0.540 AC: 36677 AN: 67936

Other (OTH) AF: 0.528 AC: 1111 AN: 2106

Alfa AF: 0.477 Hom.: 2741

Bravo AF: 0.503

Asia WGS AF: 0.638 AC: 2220 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	Deficiency of steroid 11-beta-monooxygenase (3)
-	-	3	not provided (3)
-	-	3	not specified (3)
-	-	1	Glucocorticoid-remediable aldosteronism (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	1.4
DANN	Benign	0.91
PhyloP100		-3.0
Mutation Taster		=100/0	polymorphism (auto)

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: rs6387; hg19: chr8-143958427;