rs6470

Variant names:

• chr6-32038419-C-T
• rs6470
• NM_000500.9:c.-4C>T

Variant summary

Our verdict is Benign. The variant received -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 premature start codon gain 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_premature_start_codon_gain
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -3.72
• 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 -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 VariationId is 256284.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 125 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CYP21A2	NM_000500.9	c.-4C>T		5_prime_UTR_premature_start_codon_gain_variant	Exon 1 of 10	ENST00000644719.2	NP_000491.4
CYP21A2	NM_000500.9	c.-4C>T		5_prime_UTR_variant	Exon 1 of 10	ENST00000644719.2	NP_000491.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CYP21A2	ENST00000644719.2	c.-4C>T		5_prime_UTR_premature_start_codon_gain_variant	Exon 1 of 10		NM_000500.9	ENSP00000496625.1
CYP21A2	ENST00000644719.2	c.-4C>T		5_prime_UTR_variant	Exon 1 of 10		NM_000500.9	ENSP00000496625.1

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

GnomAD2 exomes AF: 0.0123 AC: 1925 AN: 156824 AF XY: 0.0118

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 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

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

African (AFR) AF: 0.0102 AC: 319 AN: 31250

American (AMR) AF: 0.0121 AC: 438 AN: 36332

Ashkenazi Jewish (ASJ) AF: 0.0103 AC: 259 AN: 25030

East Asian (EAS) AF: 0.0197 AC: 714 AN: 36264

South Asian (SAS) AF: 0.0141 AC: 1114 AN: 78828

European-Finnish (FIN) AF: 0.0518 AC: 2455 AN: 47400

Middle Eastern (MID) AF: 0.00795 AC: 37 AN: 4656

European-Non Finnish (NFE) AF: 0.0125 AC: 12934 AN: 1030916

Other (OTH) AF: 0.0167 AC: 941 AN: 56492

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

African (AFR) AF: 0.0209 AC: 859 AN: 41116

American (AMR) AF: 0.0256 AC: 372 AN: 14544

Ashkenazi Jewish (ASJ) AF: 0.0168 AC: 57 AN: 3394

East Asian (EAS) AF: 0.0199 AC: 101 AN: 5074

South Asian (SAS) AF: 0.0282 AC: 132 AN: 4676

European-Finnish (FIN) AF: 0.0755 AC: 765 AN: 10128

Middle Eastern (MID) AF: 0.0176 AC: 5 AN: 284

European-Non Finnish (NFE) AF: 0.0437 AC: 2911 AN: 66658

Other (OTH) AF: 0.0266 AC: 55 AN: 2064

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

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

Oct 08, 2021

Quest Diagnostics Nichols Institute San Juan Capistrano

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	-0.88
CADD	Benign	0.25
DANN	Benign	0.83
PhyloP100		-3.7
PromoterAI		-0.095	Neutral
Mutation Taster		=300/0	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: rs6470; hg19: chr6-32006196; COSMIC: COSV64486547; COSMIC: COSV64486547;