rs4544

Variant names:

• chr8-142913390-A-G
• rs4544
• NM_000498.3:c.1016T>C

Your query was ambiguous. Multiple possible variants found:

• chr8-142913390-A-G
• chr8-142913390-A-T
• chr8-142913390-A-C

Variant summary

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

The NM_000498.3(CYP11B2):​c.1016T>C​(p.Ile339Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0314 in 1,613,748 control chromosomes in the GnomAD database, including 6,525 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I339V) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.12 (3327 hom., cov: 32)
  • Exomes 𝑓: 0.022 (3198 hom.)
• Consequence: CYP11B2 NM_000498.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.599
• Publications: 30 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.018127918).
• BP6: Variant 8-142913390-A-G is Benign according to our data. Variant chr8-142913390-A-G is described in ClinVar as Benign. ClinVar VariationId is 362201.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.388 is higher than 0.05.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CYP11B2	NM_000498.3	MANE Select	c.1016T>C	p.Ile339Thr	missense	Exon 6 of 9	NP_000489.3	P19099

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CYP11B2	ENST00000323110.2	TSL:1 MANE Select	c.1016T>C	p.Ile339Thr	missense	Exon 6 of 9	ENSP00000325822.2	P19099
	CYP11B2	ENST00000945895.1		c.1016T>C	p.Ile339Thr	missense	Exon 6 of 9	ENSP00000615954.1
	CYP11B2	ENST00000945896.1		c.1016T>C	p.Ile339Thr	missense	Exon 6 of 9	ENSP00000615955.1

Frequencies

GnomAD3 genomes AF: 0.121 AC: 18396 AN: 151976 Hom.: 3299 Cov.: 32

Gnomad AFR AF: 0.392

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0585

Gnomad ASJ AF: 0.00778

Gnomad EAS AF: 0.0221

Gnomad SAS AF: 0.0614

Gnomad FIN AF: 0.00518

Gnomad MID AF: 0.0633

Gnomad NFE AF: 0.00844

Gnomad OTH AF: 0.101

GnomAD2 exomes AF: 0.0455 AC: 11401 AN: 250774 AF XY: 0.0385

Gnomad AFR exome AF: 0.398

Gnomad AMR exome AF: 0.0438

Gnomad ASJ exome AF: 0.00646

Gnomad EAS exome AF: 0.0215

Gnomad FIN exome AF: 0.00434

Gnomad NFE exome AF: 0.00969

Gnomad OTH exome AF: 0.0319

GnomAD4 exome AF: 0.0221 AC: 32258 AN: 1461654 Hom.: 3198 Cov.: 37 AF XY: 0.0216 AC XY: 15685 AN XY: 727134

African (AFR) AF: 0.406 AC: 13606 AN: 33476

American (AMR) AF: 0.0452 AC: 2021 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00723 AC: 189 AN: 26136

East Asian (EAS) AF: 0.0126 AC: 499 AN: 39686

South Asian (SAS) AF: 0.0490 AC: 4223 AN: 86254

European-Finnish (FIN) AF: 0.00477 AC: 254 AN: 53232

Middle Eastern (MID) AF: 0.0437 AC: 252 AN: 5768

European-Non Finnish (NFE) AF: 0.00801 AC: 8906 AN: 1111986

Other (OTH) AF: 0.0382 AC: 2308 AN: 60392

GnomAD4 genome AF: 0.121 AC: 18474 AN: 152094 Hom.: 3327 Cov.: 32 AF XY: 0.118 AC XY: 8742 AN XY: 74356

African (AFR) AF: 0.393 AC: 16287 AN: 41448

American (AMR) AF: 0.0583 AC: 892 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00778 AC: 27 AN: 3470

East Asian (EAS) AF: 0.0221 AC: 114 AN: 5152

South Asian (SAS) AF: 0.0614 AC: 296 AN: 4820

European-Finnish (FIN) AF: 0.00518 AC: 55 AN: 10620

Middle Eastern (MID) AF: 0.0646 AC: 19 AN: 294

European-Non Finnish (NFE) AF: 0.00843 AC: 573 AN: 67974

Other (OTH) AF: 0.100 AC: 211 AN: 2110

Alfa AF: 0.0435 Hom.: 3492

Bravo AF: 0.136

TwinsUK AF: 0.00647 AC: 24

ALSPAC AF: 0.00804 AC: 31

ESP6500AA AF: 0.378 AC: 1665

ESP6500EA AF: 0.00640 AC: 55

ExAC AF: 0.0524 AC: 6364

EpiCase AF: 0.0111

EpiControl AF: 0.0107

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Corticosterone 18-monooxygenase deficiency (1)
-	-	1	Corticosterone methyl oxidase type II deficiency (1)
-	-	1	Corticosterone methyloxidase type 2 deficiency (1)
-	-	1	Glucocorticoid-remediable aldosteronism (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.085
BayesDel_addAF	Benign	-0.67	T
BayesDel_noAF	Benign	-0.59
CADD	Benign	18
DANN	Benign	0.87
DEOGEN2	Benign	0.081	T
Eigen	Benign	-1.0
Eigen_PC	Benign	-0.89
FATHMM_MKL	Benign	0.0099	N
LIST_S2	Benign	0.062	T
MetaRNN	Benign	0.018	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	-0.55	N
PhyloP100		0.60
PrimateAI	Uncertain	0.62	T
PROVEAN	Benign	1.3	N
REVEL	Benign	0.089
Sift	Benign	0.12	T
Sift4G	Benign	0.44	T
Polyphen		0.0	B
Vest4		0.024
MPC		0.29
ClinPred		0.0013	T
GERP RS		3.7
Varity_R		0.18
gMVP		0.70
Mutation Taster		=93/7	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: rs4544; hg19: chr8-143994806;