6-32039027-C-T

Variant names:

• chr6-32039027-C-T
• rs6451
• NM_000500.9:c.293-67C>T

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_Strong BS2_Supporting

The NM_000500.9(CYP21A2):​c.293-67C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00151 in 1,555,806 control chromosomes in the GnomAD database, including 26 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0018 (3 hom., cov: 31)
  • Exomes 𝑓: 0.0015 (23 hom.)
• Consequence: CYP21A2 NM_000500.9 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.107
• Publications: 11 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: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BS2: High Homozygotes in GnomAd4 at 3 AR geneVariant has number of homozygotes lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CYP21A2	NM_000500.9	c.293-67C>T		intron_variant	Intron 2 of 9	ENST00000644719.2	NP_000491.4
CYP21A2	NM_001128590.4	c.203-67C>T		intron_variant	Intron 1 of 8		NP_001122062.3
CYP21A2	NM_001368143.2	c.-132-48C>T		intron_variant	Intron 2 of 9		NP_001355072.1
CYP21A2	NM_001368144.2	c.-132-48C>T		intron_variant	Intron 1 of 8		NP_001355073.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CYP21A2	ENST00000644719.2	c.293-67C>T		intron_variant	Intron 2 of 9		NM_000500.9	ENSP00000496625.1

Frequencies

GnomAD3 genomes AF: 0.00180 AC: 273 AN: 151684 Hom.: 1 Cov.: 31

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00289

Gnomad ASJ AF: 0.00259

Gnomad EAS AF: 0.00835

Gnomad SAS AF: 0.00749

Gnomad FIN AF: 0.00701

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000854

Gnomad OTH AF: 0.00191

GnomAD2 exomes AF: 0.00328 AC: 546 AN: 166540 AF XY: 0.00342

Gnomad AFR exome AF: 0.000231

Gnomad AMR exome AF: 0.00406

Gnomad ASJ exome AF: 0.00198

Gnomad EAS exome AF: 0.00463

Gnomad FIN exome AF: 0.00789

Gnomad NFE exome AF: 0.000421

Gnomad OTH exome AF: 0.00262

GnomAD4 exome AF: 0.00147 AC: 2068 AN: 1404004 Hom.: 23 Cov.: 40 AF XY: 0.00158 AC XY: 1095 AN XY: 693618

African (AFR) AF: 0.000188 AC: 6 AN: 31852

American (AMR) AF: 0.00373 AC: 138 AN: 36980

Ashkenazi Jewish (ASJ) AF: 0.00226 AC: 57 AN: 25238

East Asian (EAS) AF: 0.0145 AC: 527 AN: 36344

South Asian (SAS) AF: 0.00678 AC: 542 AN: 79912

European-Finnish (FIN) AF: 0.00743 AC: 363 AN: 48834

Middle Eastern (MID) AF: 0.000376 AC: 2 AN: 5322

European-Non Finnish (NFE) AF: 0.000287 AC: 310 AN: 1081330

Other (OTH) AF: 0.00211 AC: 123 AN: 58192

GnomAD4 genome AF: 0.00184 AC: 279 AN: 151802 Hom.: 3 Cov.: 31 AF XY: 0.00220 AC XY: 163 AN XY: 74176

African (AFR) AF: 0.000121 AC: 5 AN: 41338

American (AMR) AF: 0.00328 AC: 50 AN: 15260

Ashkenazi Jewish (ASJ) AF: 0.00259 AC: 9 AN: 3472

East Asian (EAS) AF: 0.00837 AC: 43 AN: 5136

South Asian (SAS) AF: 0.00749 AC: 36 AN: 4804

European-Finnish (FIN) AF: 0.00701 AC: 74 AN: 10554

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

European-Non Finnish (NFE) AF: 0.000854 AC: 58 AN: 67924

Other (OTH) AF: 0.00189 AC: 4 AN: 2112

Alfa AF: 0.00167 Hom.: 114

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	0.96
DANN	Benign	0.55
PhyloP100		-0.11
Mutation Taster		=100/0	polymorphism

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: rs6451; hg19: chr6-32006804; COSMIC: COSV64477408; COSMIC: COSV64477408;