6-32039119-G-A

Variant names:

• chr6-32039119-G-A
• rs6455
• NM_000500.9:c.318G>A

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_000500.9(CYP21A2):​c.318G>A​(p.Pro106Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0016 in 1,484,242 control chromosomes in the GnomAD database, including 32 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. P106P) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.0085 (21 hom., cov: 31)
  • Exomes 𝑓: 0.00086 (11 hom.)
• Consequence: CYP21A2 NM_000500.9 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -2.25
• Publications: 13 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 6-32039119-G-A is Benign according to our data. Variant chr6-32039119-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 256292.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-2.26 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00852 (1220/143214) while in subpopulation AFR AF = 0.029 (1137/39224). AF 95% confidence interval is 0.0276. There are 21 homozygotes in GnomAd4. There are 595 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 21 AR gene

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.318G>A	p.Pro106Pro	synonymous	Exon 3 of 10	NP_000491.4
	CYP21A2	NM_001128590.4		c.228G>A	p.Pro76Pro	synonymous	Exon 2 of 9	NP_001122062.3
	CYP21A2	NM_001368143.2		c.-88G>A		5_prime_UTR	Exon 3 of 10	NP_001355072.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CYP21A2	ENST00000644719.2	MANE Select	c.318G>A	p.Pro106Pro	synonymous	Exon 3 of 10	ENSP00000496625.1
	CYP21A2	ENST00000435122.3	TSL:2	c.228G>A	p.Pro76Pro	synonymous	Exon 2 of 9	ENSP00000415043.2
	CYP21A2	ENST00000471671.4	TSL:4	c.318G>A	p.Pro106Pro	synonymous	Exon 3 of 5	ENSP00000418561.1

Frequencies

GnomAD3 genomes AF: 0.00851 AC: 1218 AN: 143104 Hom.: 21 Cov.: 31

Gnomad AFR AF: 0.0290

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00453

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000239

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000763

Gnomad OTH AF: 0.00655

GnomAD2 exomes AF: 0.00190 AC: 464 AN: 244218 AF XY: 0.00139

Gnomad AFR exome AF: 0.0245

Gnomad AMR exome AF: 0.00170

Gnomad ASJ exome AF: 0.000101

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000155

Gnomad OTH exome AF: 0.000674

GnomAD4 exome AF: 0.000858 AC: 1150 AN: 1341028 Hom.: 11 Cov.: 75 AF XY: 0.000767 AC XY: 510 AN XY: 665182

African (AFR) AF: 0.0261 AC: 786 AN: 30166

American (AMR) AF: 0.00173 AC: 72 AN: 41596

Ashkenazi Jewish (ASJ) AF: 0.0000460 AC: 1 AN: 21740

East Asian (EAS) AF: 0.0000336 AC: 1 AN: 29728

South Asian (SAS) AF: 0.000166 AC: 14 AN: 84294

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 43572

Middle Eastern (MID) AF: 0.00193 AC: 10 AN: 5188

European-Non Finnish (NFE) AF: 0.000151 AC: 156 AN: 1032490

Other (OTH) AF: 0.00211 AC: 110 AN: 52254

GnomAD4 genome AF: 0.00852 AC: 1220 AN: 143214 Hom.: 21 Cov.: 31 AF XY: 0.00858 AC XY: 595 AN XY: 69336

African (AFR) AF: 0.0290 AC: 1137 AN: 39224

American (AMR) AF: 0.00453 AC: 65 AN: 14358

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3386

East Asian (EAS) AF: 0.00 AC: 0 AN: 4346

South Asian (SAS) AF: 0.00 AC: 0 AN: 4190

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 8964

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 274

European-Non Finnish (NFE) AF: 0.0000763 AC: 5 AN: 65572

Other (OTH) AF: 0.00649 AC: 13 AN: 2002

Alfa AF: 0.000548 Hom.: 3

Bravo AF: 0.00916

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Sep 15, 2020

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	4.1
DANN	Benign	0.64
PhyloP100		-2.3
Mutation Taster		=99/1	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs6455; hg19: chr6-32006896;