rs6470

Positions:

• chr6-32038419-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000500.9(CYP21A2):​c.-4C>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0354 in 148,816 control chromosomes in the GnomAD database, including 125 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.035 (125 hom., cov: 32)
  • Exomes 𝑓: 0.014 (1197 hom.)
  • Failed GnomAD Quality Control
• Consequence: CYP21A2 NM_000500.9 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -3.72

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 (BayesDel_noAF=-0.88).
• BP6: Variant 6-32038419-C-T is Benign according to our data. Variant chr6-32038419-C-T is described in ClinVar as [Benign]. Clinvar id is 256284.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-32038419-C-T is described in Lovd as [Likely_benign]. Variant chr6-32038419-C-T is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0354 (5269/148816) while in subpopulation NFE AF= 0.0437 (2911/66658). AF 95% confidence interval is 0.0423. There are 125 homozygotes in gnomad4. There are 2667 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 125 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CYP21A2	NM_000500.9	c.-4C>T		5_prime_UTR_variant	1/10	ENST00000644719.2	NP_000491.4
CYP21A2	NM_001128590.4	c.-4C>T		5_prime_UTR_variant	1/9		NP_001122062.3
CYP21A2	NM_001368143.2	c.-428C>T		5_prime_UTR_variant	1/10		NP_001355072.1
CYP21A2	NM_001368144.2	c.-338C>T		5_prime_UTR_variant	1/9		NP_001355073.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CYP21A2	ENST00000644719.2	c.-4C>T		5_prime_UTR_variant	1/10		NM_000500.9	ENSP00000496625	P1

Frequencies

GnomAD3 genomes AF: 0.0354 AC: 5259 AN: 148700 Hom.: 123 Cov.: 32

Gnomad AFR AF: 0.0209

Gnomad AMI AF: 0.0137

Gnomad AMR AF: 0.0252

Gnomad ASJ AF: 0.0168

Gnomad EAS AF: 0.0199

Gnomad SAS AF: 0.0284

Gnomad FIN AF: 0.0755

Gnomad MID AF: 0.0163

Gnomad NFE AF: 0.0437

Gnomad OTH AF: 0.0264

GnomAD3 exomes AF: 0.0123 AC: 1925 AN: 156824 Hom.: 86 AF XY: 0.0118 AC XY: 997 AN XY: 84484

Gnomad AFR exome AF: 0.0125

Gnomad AMR exome AF: 0.00874

Gnomad ASJ exome AF: 0.00472

Gnomad EAS exome AF: 0.00953

Gnomad SAS exome AF: 0.0101

Gnomad FIN exome AF: 0.0108

Gnomad NFE exome AF: 0.0165

Gnomad OTH exome AF: 0.0129

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0143 AC: 19211 AN: 1347168 Hom.: 1197 Cov.: 30 AF XY: 0.0146 AC XY: 9710 AN XY: 666154

Gnomad4 AFR exome AF: 0.0102

Gnomad4 AMR exome AF: 0.0121

Gnomad4 ASJ exome AF: 0.0103

Gnomad4 EAS exome AF: 0.0197

Gnomad4 SAS exome AF: 0.0141

Gnomad4 FIN exome AF: 0.0518

Gnomad4 NFE exome AF: 0.0125

Gnomad4 OTH exome AF: 0.0167

GnomAD4 genome AF: 0.0354 AC: 5269 AN: 148816 Hom.: 125 Cov.: 32 AF XY: 0.0367 AC XY: 2667 AN XY: 72612

Gnomad4 AFR AF: 0.0209

Gnomad4 AMR AF: 0.0256

Gnomad4 ASJ AF: 0.0168

Gnomad4 EAS AF: 0.0199

Gnomad4 SAS AF: 0.0282

Gnomad4 FIN AF: 0.0755

Gnomad4 NFE AF: 0.0437

Gnomad4 OTH AF: 0.0266

Alfa AF: 0.0330 Hom.: 25

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

Quest Diagnostics Nichols Institute San Juan Capistrano

Oct 08, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.25
DANN	Benign	0.83

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: rs6470; hg19: chr6-32006196; COSMIC: COSV64486547; COSMIC: COSV64486547;