rs61338903

chr6-32038437-CCTG-Cchr6-32038437-CCTG-CCTGCTG

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP3 BP6_Very_Strong BA1

The NM_000500.9(CYP21A2):c.29_31del(p.Leu10del) variant causes a inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.251 in 151,604 control chromosomes in the GnomAD database, including 6,037 homozygotes. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.25 (6037 hom., cov: 24)
  • Exomes 𝑓: 0.30 (66363 hom.)
  • Failed GnomAD Quality Control
• Consequence: CYP21A2 NM_000500.9 inframe_deletion
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 1.46

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 -17 ACMG points.

• BP3: Nonframeshift variant in repetitive region in NM_000500.9
• BP6: Variant 6-32038437-CCTG-C is Benign according to our data. Variant chr6-32038437-CCTG-C is described in ClinVar as [Benign]. Clinvar id is 93160.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-32038437-CCTG-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.36 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CYP21A2	NM_000500.9	c.29_31del	p.Leu10del	inframe_deletion	1/10	ENST00000644719.2
CYP21A2	NM_001128590.4	c.29_31del	p.Leu10del	inframe_deletion	1/9
CYP21A2	NM_001368143.2	c.-396_-394del		5_prime_UTR_variant	1/10
CYP21A2	NM_001368144.2	c.-306_-304del		5_prime_UTR_variant	1/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CYP21A2	ENST00000644719.2	c.29_31del	p.Leu10del	inframe_deletion	1/10		NM_000500.9	P1

Frequencies

GnomAD3 genomes AF: 0.251 AC: 38005 AN: 151486 Hom.: 6030 Cov.: 24

Gnomad AFR AF: 0.0653

Gnomad AMI AF: 0.425

Gnomad AMR AF: 0.368

Gnomad ASJ AF: 0.462

Gnomad EAS AF: 0.198

Gnomad SAS AF: 0.239

Gnomad FIN AF: 0.349

Gnomad MID AF: 0.340

Gnomad NFE AF: 0.314

Gnomad OTH AF: 0.250

GnomAD3 exomes AF: 0.309 AC: 48291 AN: 156350 Hom.: 8560 AF XY: 0.302 AC XY: 25385 AN XY: 84000

Gnomad AFR exome AF: 0.0530

Gnomad AMR exome AF: 0.436

Gnomad ASJ exome AF: 0.460

Gnomad EAS exome AF: 0.185

Gnomad SAS exome AF: 0.243

Gnomad FIN exome AF: 0.339

Gnomad NFE exome AF: 0.309

Gnomad OTH exome AF: 0.308

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.299 AC: 419054 AN: 1401396 Hom.: 66363 AF XY: 0.299 AC XY: 207021 AN XY: 691912

Gnomad4 AFR exome AF: 0.0611

Gnomad4 AMR exome AF: 0.426

Gnomad4 ASJ exome AF: 0.451

Gnomad4 EAS exome AF: 0.240

Gnomad4 SAS exome AF: 0.248

Gnomad4 FIN exome AF: 0.339

Gnomad4 NFE exome AF: 0.303

Gnomad4 OTH exome AF: 0.285

GnomAD4 genome AF: 0.251 AC: 38018 AN: 151604 Hom.: 6037 Cov.: 24 AF XY: 0.254 AC XY: 18835 AN XY: 74048

Gnomad4 AFR AF: 0.0651

Gnomad4 AMR AF: 0.368

Gnomad4 ASJ AF: 0.462

Gnomad4 EAS AF: 0.199

Gnomad4 SAS AF: 0.239

Gnomad4 FIN AF: 0.349

Gnomad4 NFE AF: 0.314

Gnomad4 OTH AF: 0.251

Alfa AF: 0.228 Hom.: 952

Bravo AF: 0.247

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 21, 2013	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Athena Diagnostics

Jul 18, 2017

- -

Computational scores

Source: dbNSFP v4.3

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: rs61338903; hg19: chr6-32006214;