rs6469

Variant names:

• chr6-32040674-C-T
• rs6469
• NM_000500.9:c.1125C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000500.9(CYP21A2):​c.1125C>T​(p.Ser375Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.166 in 146,200 control chromosomes in the GnomAD database, including 439 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.17 (439 hom., cov: 33)
  • Exomes 𝑓: 0.16 (3961 hom.)
  • Failed GnomAD Quality Control
• Consequence: CYP21A2 NM_000500.9 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -5.43
• Publications: 7 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=-0.95).
• BP6: Variant 6-32040674-C-T is Benign according to our data. Variant chr6-32040674-C-T is described in ClinVar as Benign. ClinVar VariationId is 256285.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-5.43 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.253 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CYP21A2	NM_000500.9	c.1125C>T	p.Ser375Ser	synonymous_variant	Exon 9 of 10	ENST00000644719.2	NP_000491.4
CYP21A2	NM_001128590.4	c.1035C>T	p.Ser345Ser	synonymous_variant	Exon 8 of 9		NP_001122062.3
CYP21A2	NM_001368143.2	c.720C>T	p.Ser240Ser	synonymous_variant	Exon 9 of 10		NP_001355072.1
CYP21A2	NM_001368144.2	c.720C>T	p.Ser240Ser	synonymous_variant	Exon 8 of 9		NP_001355073.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CYP21A2	ENST00000644719.2	c.1125C>T	p.Ser375Ser	synonymous_variant	Exon 9 of 10		NM_000500.9	ENSP00000496625.1

Frequencies

GnomAD3 genomes AF: 0.166 AC: 24206 AN: 146080 Hom.: 441 Cov.: 33

Gnomad AFR AF: 0.131

Gnomad AMI AF: 0.316

Gnomad AMR AF: 0.259

Gnomad ASJ AF: 0.279

Gnomad EAS AF: 0.108

Gnomad SAS AF: 0.162

Gnomad FIN AF: 0.149

Gnomad MID AF: 0.151

Gnomad NFE AF: 0.166

Gnomad OTH AF: 0.171

GnomAD2 exomes AF: 0.180 AC: 39587 AN: 219336 AF XY: 0.176

Gnomad AFR exome AF: 0.134

Gnomad AMR exome AF: 0.316

Gnomad ASJ exome AF: 0.282

Gnomad EAS exome AF: 0.0971

Gnomad FIN exome AF: 0.144

Gnomad NFE exome AF: 0.163

Gnomad OTH exome AF: 0.175

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.164 AC: 228468 AN: 1390034 Hom.: 3961 Cov.: 34 AF XY: 0.164 AC XY: 113449 AN XY: 691930

African (AFR) AF: 0.138 AC: 4456 AN: 32302

American (AMR) AF: 0.311 AC: 13077 AN: 41996

Ashkenazi Jewish (ASJ) AF: 0.271 AC: 6412 AN: 23680

East Asian (EAS) AF: 0.140 AC: 5432 AN: 38836

South Asian (SAS) AF: 0.157 AC: 12404 AN: 78892

European-Finnish (FIN) AF: 0.149 AC: 7811 AN: 52346

Middle Eastern (MID) AF: 0.139 AC: 750 AN: 5384

European-Non Finnish (NFE) AF: 0.159 AC: 168656 AN: 1059658

Other (OTH) AF: 0.166 AC: 9470 AN: 56940

GnomAD4 genome AF: 0.166 AC: 24235 AN: 146200 Hom.: 439 Cov.: 33 AF XY: 0.166 AC XY: 11866 AN XY: 71394

African (AFR) AF: 0.131 AC: 5287 AN: 40230

American (AMR) AF: 0.259 AC: 3712 AN: 14306

Ashkenazi Jewish (ASJ) AF: 0.279 AC: 873 AN: 3126

East Asian (EAS) AF: 0.108 AC: 540 AN: 4992

South Asian (SAS) AF: 0.162 AC: 711 AN: 4388

European-Finnish (FIN) AF: 0.149 AC: 1544 AN: 10374

Middle Eastern (MID) AF: 0.160 AC: 45 AN: 282

European-Non Finnish (NFE) AF: 0.166 AC: 10902 AN: 65628

Other (OTH) AF: 0.171 AC: 337 AN: 1974

Alfa AF: 0.189 Hom.: 73

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

May 15, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	4.9
DANN	Benign	0.89
PhyloP100		-5.4
Mutation Taster		=100/0	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: rs6469; hg19: chr6-32008451; COSMIC: COSV64473267; COSMIC: COSV64473267;