6-32040072-G-C

Variant names:

• chr6-32040072-G-C
• rs6472
• NM_000500.9:c.806G>C

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 3P and 20B. PM1 PP2 BP4_Strong BP6_Very_Strong BA1

The NM_000500.9(CYP21A2):​c.806G>C​(p.Ser269Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.112 in 1,536,460 control chromosomes in the GnomAD database, including 9,528 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.13 (1536 hom., cov: 32)
  • Exomes 𝑓: 0.11 (7992 hom.)
• Consequence: CYP21A2 NM_000500.9 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6 O:2
• Conservation: PhyloP100: -0.979
• Publications: 33 publications found

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]

CYP21A2 Gene-Disease associations (from GenCC):

• classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Myriad Women’s Health, Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine
• classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency, salt wasting form

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency, simple virilizing form

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -17 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 3 uncertain in NM_000500.9
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 52 curated pathogenic missense variants (we use a threshold of 10). The gene has 5 curated benign missense variants. Trascript score misZ: 1.8021 (below the threshold of 3.09). GenCC associations: The gene is linked to classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency, simple virilizing form, classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency, classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency, salt wasting form.
• BP4: Computational evidence support a benign effect (MetaRNN=0.013784409).
• BP6: Variant 6-32040072-G-C is Benign according to our data. Variant chr6-32040072-G-C is described in ClinVar as Benign. ClinVar VariationId is 12154.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.216 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000500.9. 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
	CYP21A2	NM_000500.9	MANE Select	c.806G>C	p.Ser269Thr	missense	Exon 7 of 10	NP_000491.4
	CYP21A2	NM_001128590.4		c.716G>C	p.Ser239Thr	missense	Exon 6 of 9	NP_001122062.3
	CYP21A2	NM_001368143.2		c.401G>C	p.Ser134Thr	missense	Exon 7 of 10	NP_001355072.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CYP21A2	ENST00000644719.2	MANE Select	c.806G>C	p.Ser269Thr	missense	Exon 7 of 10	ENSP00000496625.1
	CYP21A2	ENST00000435122.3	TSL:2	c.716G>C	p.Ser239Thr	missense	Exon 6 of 9	ENSP00000415043.2
	CYP21A2	ENST00000479074.5	TSL:3	n.864G>C		non_coding_transcript_exon	Exon 7 of 9

Frequencies

GnomAD3 genomes AF: 0.135 AC: 20079 AN: 149138 Hom.: 1530 Cov.: 32

Gnomad AFR AF: 0.220

Gnomad AMI AF: 0.0166

Gnomad AMR AF: 0.136

Gnomad ASJ AF: 0.106

Gnomad EAS AF: 0.0992

Gnomad SAS AF: 0.217

Gnomad FIN AF: 0.0620

Gnomad MID AF: 0.209

Gnomad NFE AF: 0.0939

Gnomad OTH AF: 0.166

GnomAD2 exomes AF: 0.129 AC: 30937 AN: 238976 AF XY: 0.136

Gnomad AFR exome AF: 0.252

Gnomad AMR exome AF: 0.0932

Gnomad ASJ exome AF: 0.102

Gnomad EAS exome AF: 0.105

Gnomad FIN exome AF: 0.0668

Gnomad NFE exome AF: 0.108

Gnomad OTH exome AF: 0.134

GnomAD4 exome AF: 0.109 AC: 151700 AN: 1387202 Hom.: 7992 Cov.: 89 AF XY: 0.113 AC XY: 78540 AN XY: 692024

African (AFR) AF: 0.248 AC: 7522 AN: 30298

American (AMR) AF: 0.0969 AC: 4185 AN: 43208

Ashkenazi Jewish (ASJ) AF: 0.103 AC: 2660 AN: 25854

East Asian (EAS) AF: 0.106 AC: 4197 AN: 39556

South Asian (SAS) AF: 0.246 AC: 21183 AN: 86096

European-Finnish (FIN) AF: 0.0687 AC: 3578 AN: 52118

Middle Eastern (MID) AF: 0.195 AC: 1103 AN: 5666

European-Non Finnish (NFE) AF: 0.0958 AC: 100277 AN: 1046754

Other (OTH) AF: 0.121 AC: 6995 AN: 57652

GnomAD4 genome AF: 0.135 AC: 20106 AN: 149258 Hom.: 1536 Cov.: 32 AF XY: 0.137 AC XY: 9981 AN XY: 73048

African (AFR) AF: 0.220 AC: 8817 AN: 40074

American (AMR) AF: 0.135 AC: 2028 AN: 14968

Ashkenazi Jewish (ASJ) AF: 0.106 AC: 366 AN: 3452

East Asian (EAS) AF: 0.0995 AC: 510 AN: 5128

South Asian (SAS) AF: 0.215 AC: 1033 AN: 4796

European-Finnish (FIN) AF: 0.0620 AC: 657 AN: 10594

Middle Eastern (MID) AF: 0.194 AC: 57 AN: 294

European-Non Finnish (NFE) AF: 0.0939 AC: 6290 AN: 67010

Other (OTH) AF: 0.164 AC: 333 AN: 2036

Alfa AF: 0.0734 Hom.: 95

Bravo AF: 0.142

ESP6500AA AF: 0.219 AC: 662

ESP6500EA AF: 0.0978 AC: 530

ExAC AF: 0.151 AC: 18188

Asia WGS AF: 0.231 AC: 804 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:6 Other:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Mar 29, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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

Apr 13, 2017

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

not provided Benign:1

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

21-HYDROXYLASE POLYMORPHISM Benign:1

Aug 01, 1991

OMIM

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: literature only

Congenital adrenal hyperplasia Other:1

Oct 02, 2015

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: not provided

Review Status: no classification provided

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.083
BayesDel_addAF	Benign	-0.65	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	0.15
DANN	Benign	0.66
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.050	N
MetaRNN	Benign	0.014	T
MetaSVM	Benign	-1.0	T
PhyloP100		-0.98
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.064
Sift	Benign	0.33	T
Sift4G	Benign	0.60	T
Polyphen		0.022	B
Vest4		0.041
MPC		0.43
ClinPred		0.0022	T
GERP RS		-3.0
gMVP		0.22
Mutation Taster		=92/8	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: rs6472; hg19: chr6-32007849; COSMIC: COSV64483668; COSMIC: COSV64483668;