6-32038115-G-C

Variant names:

• chr6-32038115-G-C
• rs3130676
• ENST00000466779.5:n.-308G>C

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BS1_Supporting BS2

The ENST00000479074.5(CYP21A2):​n.-250G>C variant causes a upstream gene change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00381 in 585,066 control chromosomes in the GnomAD database, including 25 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0083 (15 hom., cov: 32)
  • Exomes 𝑓: 0.0022 (10 hom.)
• Consequence: CYP21A2 ENST00000479074.5 upstream_gene
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -2.72
• Publications: 2 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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00831 (1263/152060) while in subpopulation AFR AF = 0.0258 (1071/41452). AF 95% confidence interval is 0.0246. There are 15 homozygotes in GnomAd4. There are 620 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAd4 at 15 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000479074.5. 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
There are no transcript annotations for this variant.

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CYP21A2	ENST00000466779.5	TSL:5	n.-308G>C		upstream_gene	N/A	ENSP00000417321.1
	CYP21A2	ENST00000479074.5	TSL:3	n.-250G>C		upstream_gene	N/A
	CYP21A2	ENST00000479730.5	TSL:5	n.-250G>C		upstream_gene	N/A

Frequencies

GnomAD3 genomes AF: 0.00827 AC: 1257 AN: 151942 Hom.: 15 Cov.: 32

Gnomad AFR AF: 0.0258

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00563

Gnomad ASJ AF: 0.00980

Gnomad EAS AF: 0.000578

Gnomad SAS AF: 0.00103

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000648

Gnomad OTH AF: 0.00911

GnomAD4 exome AF: 0.00224 AC: 969 AN: 433006 Hom.: 10 AF XY: 0.00209 AC XY: 471 AN XY: 225384

African (AFR) AF: 0.0244 AC: 301 AN: 12330

American (AMR) AF: 0.00501 AC: 83 AN: 16564

Ashkenazi Jewish (ASJ) AF: 0.00773 AC: 98 AN: 12678

East Asian (EAS) AF: 0.00420 AC: 117 AN: 27864

South Asian (SAS) AF: 0.00160 AC: 68 AN: 42584

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 24280

Middle Eastern (MID) AF: 0.00725 AC: 14 AN: 1930

European-Non Finnish (NFE) AF: 0.000619 AC: 167 AN: 269994

Other (OTH) AF: 0.00488 AC: 121 AN: 24782

GnomAD4 genome AF: 0.00831 AC: 1263 AN: 152060 Hom.: 15 Cov.: 32 AF XY: 0.00834 AC XY: 620 AN XY: 74376

African (AFR) AF: 0.0258 AC: 1071 AN: 41452

American (AMR) AF: 0.00563 AC: 86 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.00980 AC: 34 AN: 3468

East Asian (EAS) AF: 0.000579 AC: 3 AN: 5178

South Asian (SAS) AF: 0.00124 AC: 6 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10606

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.000648 AC: 44 AN: 67930

Other (OTH) AF: 0.00901 AC: 19 AN: 2108

Alfa AF: 0.000364 Hom.: 0

Bravo AF: 0.0103

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.020
DANN	Benign	0.79
PhyloP100		-2.7
PromoterAI		0.053	Neutral

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs3130676; hg19: chr6-32005892;