chr8-142875735-A-C

Variant names:

• chr8-142875735-A-C
• rs61752769
• NM_000497.4:c.1098T>G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000497.4(CYP11B1):​c.1098T>G​(p.Arg366Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00482 in 1,599,246 control chromosomes in the GnomAD database, including 108 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.019 (53 hom., cov: 31)
  • Exomes 𝑓: 0.0035 (55 hom.)
• Consequence: CYP11B1 NM_000497.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.00200
• Publications: 4 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.67).
• BP6: Variant 8-142875735-A-C is Benign according to our data. Variant chr8-142875735-A-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 362150.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.002 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0567 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CYP11B1	NM_000497.4	MANE Select	c.1098T>G	p.Arg366Arg	synonymous	Exon 6 of 9	NP_000488.3
	CYP11B1	NM_001026213.1		c.1098T>G	p.Arg366Arg	synonymous	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.1098T>G	p.Arg366Arg	synonymous	Exon 6 of 9	ENSP00000292427.5	P15538-1
	CYP11B1	ENST00000377675.3	TSL:1	c.1311T>G	p.Arg437Arg	synonymous	Exon 8 of 11	ENSP00000366903.3	Q4VAR0
	CYP11B1	ENST00000517471.5	TSL:1	c.1098T>G	p.Arg366Arg	synonymous	Exon 6 of 8	ENSP00000428043.1	P15538-2

Frequencies

GnomAD3 genomes AF: 0.0192 AC: 2662 AN: 138716 Hom.: 53 Cov.: 31

Gnomad AFR AF: 0.0589

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0107

Gnomad ASJ AF: 0.00459

Gnomad EAS AF: 0.00693

Gnomad SAS AF: 0.0121

Gnomad FIN AF: 0.00315

Gnomad MID AF: 0.0317

Gnomad NFE AF: 0.00371

Gnomad OTH AF: 0.0151

GnomAD2 exomes AF: 0.00608 AC: 1519 AN: 249754 AF XY: 0.00537

Gnomad AFR exome AF: 0.0467

Gnomad AMR exome AF: 0.00506

Gnomad ASJ exome AF: 0.00229

Gnomad EAS exome AF: 0.00262

Gnomad FIN exome AF: 0.000278

Gnomad NFE exome AF: 0.00252

Gnomad OTH exome AF: 0.00359

GnomAD4 exome AF: 0.00346 AC: 5050 AN: 1460442 Hom.: 55 Cov.: 33 AF XY: 0.00345 AC XY: 2510 AN XY: 726556

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0445 AC: 1479 AN: 33238

American (AMR) AF: 0.00472 AC: 211 AN: 44680

Ashkenazi Jewish (ASJ) AF: 0.00203 AC: 53 AN: 26096

East Asian (EAS) AF: 0.00470 AC: 186 AN: 39538

South Asian (SAS) AF: 0.00637 AC: 549 AN: 86208

European-Finnish (FIN) AF: 0.000338 AC: 18 AN: 53332

Middle Eastern (MID) AF: 0.00643 AC: 37 AN: 5754

European-Non Finnish (NFE) AF: 0.00199 AC: 2210 AN: 1111272

Other (OTH) AF: 0.00509 AC: 307 AN: 60324

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0192 AC: 2666 AN: 138804 Hom.: 53 Cov.: 31 AF XY: 0.0191 AC XY: 1294 AN XY: 67696

African (AFR) AF: 0.0588 AC: 2115 AN: 35948

American (AMR) AF: 0.0107 AC: 149 AN: 13936

Ashkenazi Jewish (ASJ) AF: 0.00459 AC: 15 AN: 3268

East Asian (EAS) AF: 0.00695 AC: 30 AN: 4318

South Asian (SAS) AF: 0.0120 AC: 51 AN: 4234

European-Finnish (FIN) AF: 0.00315 AC: 31 AN: 9830

Middle Eastern (MID) AF: 0.0303 AC: 8 AN: 264

European-Non Finnish (NFE) AF: 0.00371 AC: 238 AN: 64172

Other (OTH) AF: 0.0149 AC: 29 AN: 1942

Alfa AF: 0.00960 Hom.: 12

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	Deficiency of steroid 11-beta-monooxygenase (1)
-	-	1	Deficiency of steroid 11-beta-monooxygenase;C3838731:Glucocorticoid-remediable aldosteronism (1)
-	-	1	Glucocorticoid-remediable aldosteronism (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.67
CADD	Benign	7.5
DANN	Benign	0.65
PhyloP100		-0.0020
PromoterAI		-0.021	Neutral
Mutation Taster		=99/1	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: rs61752769; hg19: chr8-143957151; COSMIC: COSV52824756;