rs6442

Variant names:

• chr6-32040216-G-C
• rs6442
• NM_000500.9:c.939+11G>C

Your query was ambiguous. Multiple possible variants found:

• chr6-32040216-G-C
• chr6-32040216-G-A

Variant summary

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

The NM_000500.9(CYP21A2):​c.939+11G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00765 in 1,609,538 control chromosomes in the GnomAD database, including 371 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0083 (38 hom., cov: 33)
  • Exomes 𝑓: 0.0076 (333 hom.)
• Consequence: CYP21A2 NM_000500.9 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.61
• Publications: 3 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: Labcorp Genetics (formerly Invitae), Myriad Women’s Health, 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 6-32040216-G-C is Benign according to our data. Variant chr6-32040216-G-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 256303.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0846 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CYP21A2	NM_000500.9	MANE Select	c.939+11G>C		intron	N/A	NP_000491.4
	CYP21A2	NM_001128590.4		c.849+11G>C		intron	N/A	NP_001122062.3	P08686-2
	CYP21A2	NM_001368143.2		c.534+11G>C		intron	N/A	NP_001355072.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CYP21A2	ENST00000644719.2	MANE Select	c.939+11G>C		intron	N/A	ENSP00000496625.1	P08686-1
	CYP21A2	ENST00000960600.1		c.975+11G>C		intron	N/A	ENSP00000630659.1
	CYP21A2	ENST00000960597.1		c.948+11G>C		intron	N/A	ENSP00000630656.1

Frequencies

GnomAD3 genomes AF: 0.00834 AC: 1259 AN: 150870 Hom.: 38 Cov.: 33

Gnomad AFR AF: 0.00162

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00912

Gnomad ASJ AF: 0.000868

Gnomad EAS AF: 0.0909

Gnomad SAS AF: 0.00608

Gnomad FIN AF: 0.0259

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00400

Gnomad OTH AF: 0.00727

GnomAD2 exomes AF: 0.0144 AC: 3548 AN: 246188 AF XY: 0.0131

Gnomad AFR exome AF: 0.00146

Gnomad AMR exome AF: 0.0209

Gnomad ASJ exome AF: 0.00160

Gnomad EAS exome AF: 0.0896

Gnomad FIN exome AF: 0.0226

Gnomad NFE exome AF: 0.00398

Gnomad OTH exome AF: 0.00858

GnomAD4 exome AF: 0.00758 AC: 11054 AN: 1458554 Hom.: 333 Cov.: 38 AF XY: 0.00748 AC XY: 5425 AN XY: 725624

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

African (AFR) AF: 0.00108 AC: 36 AN: 33444

American (AMR) AF: 0.0146 AC: 647 AN: 44226

Ashkenazi Jewish (ASJ) AF: 0.000881 AC: 23 AN: 26120

East Asian (EAS) AF: 0.108 AC: 4251 AN: 39410

South Asian (SAS) AF: 0.00463 AC: 398 AN: 86028

European-Finnish (FIN) AF: 0.0199 AC: 1041 AN: 52266

Middle Eastern (MID) AF: 0.00574 AC: 33 AN: 5750

European-Non Finnish (NFE) AF: 0.00373 AC: 4149 AN: 1111064

Other (OTH) AF: 0.00790 AC: 476 AN: 60246

⚠️ 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: 0.00833 AC: 1257 AN: 150984 Hom.: 38 Cov.: 33 AF XY: 0.00949 AC XY: 700 AN XY: 73770

African (AFR) AF: 0.00161 AC: 66 AN: 40934

American (AMR) AF: 0.00904 AC: 137 AN: 15148

Ashkenazi Jewish (ASJ) AF: 0.000868 AC: 3 AN: 3456

East Asian (EAS) AF: 0.0915 AC: 465 AN: 5082

South Asian (SAS) AF: 0.00587 AC: 28 AN: 4766

European-Finnish (FIN) AF: 0.0259 AC: 272 AN: 10518

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00398 AC: 270 AN: 67792

Other (OTH) AF: 0.00720 AC: 15 AN: 2084

Alfa AF: 0.00525 Hom.: 0

Bravo AF: 0.00731

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not specified (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	15
DANN	Benign	0.66
PhyloP100		1.6
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs6442; hg19: chr6-32007993;