6-32038115-G-T

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4_Strong BP6_Moderate BS2_Supporting

The ENST00000466779.5(CYP21A2):​n.-308G>T variant causes a upstream gene change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00162 in 585,250 control chromosomes in the GnomAD database, including 11 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0012 (3 hom., cov: 32)
  • Exomes 𝑓: 0.0018 (8 hom.)
• Consequence: CYP21A2 ENST00000466779.5 upstream_gene
• Clinical Significance: Likely benign criteria provided, single submitter B: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 -7 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 6-32038115-G-T is Benign according to our data. Variant chr6-32038115-G-T is described in ClinVar as Likely_benign. ClinVar VariationId is 2656438.Status of the report is criteria_provided_single_submitter, 1 stars.
• 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000466779.5. 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>T		upstream_gene	N/A	ENSP00000417321.1
	CYP21A2	ENST00000479074.5	TSL:3	n.-250G>T		upstream_gene	N/A
	CYP21A2	ENST00000479730.5	TSL:5	n.-250G>T		upstream_gene	N/A

Frequencies

GnomAD3 genomes AF: 0.00122 AC: 186 AN: 151998 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00124

Gnomad ASJ AF: 0.000865

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00352

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00197

Gnomad OTH AF: 0.000959

GnomAD4 exome AF: 0.00176 AC: 761 AN: 433134 Hom.: 8 AF XY: 0.00206 AC XY: 465 AN XY: 225442

African (AFR) AF: 0.00 AC: 0 AN: 12338

American (AMR) AF: 0.00139 AC: 23 AN: 16568

Ashkenazi Jewish (ASJ) AF: 0.00118 AC: 15 AN: 12692

East Asian (EAS) AF: 0.00 AC: 0 AN: 27956

South Asian (SAS) AF: 0.00531 AC: 226 AN: 42580

European-Finnish (FIN) AF: 0.0000824 AC: 2 AN: 24280

Middle Eastern (MID) AF: 0.00674 AC: 13 AN: 1930

European-Non Finnish (NFE) AF: 0.00161 AC: 435 AN: 270004

Other (OTH) AF: 0.00190 AC: 47 AN: 24786

GnomAD4 genome AF: 0.00122 AC: 186 AN: 152116 Hom.: 3 Cov.: 32 AF XY: 0.00134 AC XY: 100 AN XY: 74400

African (AFR) AF: 0.000241 AC: 10 AN: 41490

American (AMR) AF: 0.00124 AC: 19 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.000865 AC: 3 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5180

South Asian (SAS) AF: 0.00352 AC: 17 AN: 4832

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

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

European-Non Finnish (NFE) AF: 0.00197 AC: 134 AN: 67938

Other (OTH) AF: 0.000949 AC: 2 AN: 2108

Alfa AF: 0.0000606 Hom.: 0

Bravo AF: 0.00121

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

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	-0.88
CADD	Benign	0.020
DANN	Benign	0.87
PhyloP100		-2.7
PromoterAI		0.048	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;