rs6474

chr6-32039109-G-Achr6-32039109-G-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000500.9(CYP21A2):c.308G>A(p.Arg103Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.305 in 1,595,216 control chromosomes in the GnomAD database, including 79,844 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.26 (6406 hom., cov: 30)
  • Exomes 𝑓: 0.31 (73438 hom.)
• Consequence: CYP21A2 NM_000500.9 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3 O:1
• Conservation: PhyloP100: -0.600

Genes affected

CYP21A2 (HGNC:2600): (cytochrome P450 family 21 subfamily A 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 endoplasmic reticulum and hydroxylates steroids at the 21 position. Its activity is required for the synthesis of steroid hormones including cortisol and aldosterone. Mutations in this gene cause congenital adrenal hyperplasia. A related pseudogene is located near this gene; gene conversion events involving the functional gene and the pseudogene are thought to account for many cases of steroid 21-hydroxylase deficiency. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=5.930662E-4).
• BP6: Variant 6-32039109-G-A is Benign according to our data. Variant chr6-32039109-G-A is described in ClinVar as [Benign]. Clinvar id is 65608.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-32039109-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.366 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CYP21A2	NM_000500.9	c.308G>A	p.Arg103Lys	missense_variant	3/10	ENST00000644719.2
CYP21A2	NM_001128590.4	c.218G>A	p.Arg73Lys	missense_variant	2/9
CYP21A2	NM_001368143.2	c.-98G>A		5_prime_UTR_variant	3/10
CYP21A2	NM_001368144.2	c.-98G>A		5_prime_UTR_variant	2/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CYP21A2	ENST00000644719.2	c.308G>A	p.Arg103Lys	missense_variant	3/10		NM_000500.9	P1

Frequencies

GnomAD3 genomes AF: 0.257 AC: 38624 AN: 150542 Hom.: 6397 Cov.: 30

Gnomad AFR AF: 0.0587

Gnomad AMI AF: 0.477

Gnomad AMR AF: 0.373

Gnomad ASJ AF: 0.457

Gnomad EAS AF: 0.206

Gnomad SAS AF: 0.229

Gnomad FIN AF: 0.387

Gnomad MID AF: 0.340

Gnomad NFE AF: 0.323

Gnomad OTH AF: 0.254

GnomAD3 exomes AF: 0.316 AC: 75713 AN: 239240 Hom.: 13678 AF XY: 0.314 AC XY: 40568 AN XY: 129016

Gnomad AFR exome AF: 0.0484

Gnomad AMR exome AF: 0.448

Gnomad ASJ exome AF: 0.458

Gnomad EAS exome AF: 0.190

Gnomad SAS exome AF: 0.231

Gnomad FIN exome AF: 0.380

Gnomad NFE exome AF: 0.333

Gnomad OTH exome AF: 0.319

GnomAD4 exome AF: 0.310 AC: 447411 AN: 1444554 Hom.: 73438 Cov.: 83 AF XY: 0.310 AC XY: 222057 AN XY: 717456

Gnomad4 AFR exome AF: 0.0499

Gnomad4 AMR exome AF: 0.440

Gnomad4 ASJ exome AF: 0.450

Gnomad4 EAS exome AF: 0.269

Gnomad4 SAS exome AF: 0.236

Gnomad4 FIN exome AF: 0.380

Gnomad4 NFE exome AF: 0.314

Gnomad4 OTH exome AF: 0.293

GnomAD4 genome AF: 0.256 AC: 38642 AN: 150662 Hom.: 6406 Cov.: 30 AF XY: 0.261 AC XY: 19189 AN XY: 73518

Gnomad4 AFR AF: 0.0585

Gnomad4 AMR AF: 0.374

Gnomad4 ASJ AF: 0.457

Gnomad4 EAS AF: 0.206

Gnomad4 SAS AF: 0.229

Gnomad4 FIN AF: 0.387

Gnomad4 NFE AF: 0.323

Gnomad4 OTH AF: 0.256

Alfa AF: 0.271 Hom.: 3224

Bravo AF: 0.248

TwinsUK AF: 0.317 AC: 1176

ALSPAC AF: 0.307 AC: 1183

ESP6500AA AF: 0.0693 AC: 305

ESP6500EA AF: 0.315 AC: 2705

ExAC AF: 0.300 AC: 36377

Asia WGS AF: 0.221 AC: 769 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency Benign:1 Other:1

not provided, no classification provided	literature only	GeneReviews	-	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 30, 2021	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Athena Diagnostics

Jul 18, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.61	T
BayesDel_noAF	Benign	-0.51
Cadd	Benign	0.090
Dann	Benign	0.63
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.0013	N
MetaRNN	Benign	0.00059	T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	1.0	P;P
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-0.86	N;.;N;N;N;.
REVEL	Benign	0.068
Sift	Benign	0.49	T;.;T;T;T;.
Sift4G	Benign	1.0	T;.;T;T;T;.
Polyphen		0.0	B;B;.;.;.;B
Vest4		0.024
MPC		0.47
ClinPred		0.0043	T
GERP RS		-4.4
gMVP		0.30

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

Publications

LitVar

Other links and lift over

dbSNP: rs6474; hg19: chr6-32006886; COSMIC: COSV64476105; COSMIC: COSV64476105;