chr6-32038540-C-T

Variant names:

• chr6-32038540-C-T
• rs6468
• NM_000500.9:c.118C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000500.9(CYP21A2):​c.118C>T​(p.Leu40Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.833 in 150,170 control chromosomes in the GnomAD database, including 51,682 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.83 (51682 hom., cov: 30)
  • Exomes 𝑓: 0.79 (439449 hom.)
  • Failed GnomAD Quality Control
• Consequence: CYP21A2 NM_000500.9 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.0860
• Publications: 12 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.58).
• BP6: Variant 6-32038540-C-T is Benign according to our data. Variant chr6-32038540-C-T is described in ClinVar as Benign. ClinVar VariationId is 256286.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.086 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.901 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000500.9. 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
	CYP21A2	NM_000500.9	MANE Select	c.118C>T	p.Leu40Leu	synonymous	Exon 1 of 10	NP_000491.4
	CYP21A2	NM_001368143.2		c.-307C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 10	NP_001355072.1
	CYP21A2	NM_001368144.2		c.-217C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 9	NP_001355073.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CYP21A2	ENST00000644719.2	MANE Select	c.118C>T	p.Leu40Leu	synonymous	Exon 1 of 10	ENSP00000496625.1
	CYP21A2	ENST00000435122.3	TSL:2	c.118C>T	p.Leu40Leu	synonymous	Exon 1 of 9	ENSP00000415043.2
	CYP21A2	ENST00000471671.4	TSL:4	c.118C>T	p.Leu40Leu	synonymous	Exon 1 of 5	ENSP00000418561.1

Frequencies

GnomAD3 genomes AF: 0.833 AC: 124960 AN: 150056 Hom.: 51626 Cov.: 30

Gnomad AFR AF: 0.908

Gnomad AMI AF: 0.916

Gnomad AMR AF: 0.846

Gnomad ASJ AF: 0.893

Gnomad EAS AF: 0.751

Gnomad SAS AF: 0.823

Gnomad FIN AF: 0.816

Gnomad MID AF: 0.890

Gnomad NFE AF: 0.789

Gnomad OTH AF: 0.846

GnomAD2 exomes AF: 0.794 AC: 182802 AN: 230114 AF XY: 0.793

Gnomad AFR exome AF: 0.885

Gnomad AMR exome AF: 0.842

Gnomad ASJ exome AF: 0.874

Gnomad EAS exome AF: 0.710

Gnomad FIN exome AF: 0.791

Gnomad NFE exome AF: 0.769

Gnomad OTH exome AF: 0.790

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.787 AC: 1141026 AN: 1450538 Hom.: 439449 Cov.: 121 AF XY: 0.787 AC XY: 567343 AN XY: 720666

African (AFR) AF: 0.904 AC: 30009 AN: 33198

American (AMR) AF: 0.846 AC: 36718 AN: 43406

Ashkenazi Jewish (ASJ) AF: 0.881 AC: 22813 AN: 25900

East Asian (EAS) AF: 0.723 AC: 28431 AN: 39318

South Asian (SAS) AF: 0.813 AC: 69105 AN: 84980

European-Finnish (FIN) AF: 0.790 AC: 41249 AN: 52244

Middle Eastern (MID) AF: 0.803 AC: 4581 AN: 5704

European-Non Finnish (NFE) AF: 0.778 AC: 860689 AN: 1105900

Other (OTH) AF: 0.792 AC: 47431 AN: 59888

GnomAD4 genome AF: 0.833 AC: 125073 AN: 150170 Hom.: 51682 Cov.: 30 AF XY: 0.832 AC XY: 61039 AN XY: 73322

African (AFR) AF: 0.909 AC: 37015 AN: 40738

American (AMR) AF: 0.846 AC: 12778 AN: 15096

Ashkenazi Jewish (ASJ) AF: 0.893 AC: 3081 AN: 3452

East Asian (EAS) AF: 0.752 AC: 3742 AN: 4978

South Asian (SAS) AF: 0.822 AC: 3926 AN: 4774

European-Finnish (FIN) AF: 0.816 AC: 8519 AN: 10438

Middle Eastern (MID) AF: 0.886 AC: 257 AN: 290

European-Non Finnish (NFE) AF: 0.789 AC: 53162 AN: 67418

Other (OTH) AF: 0.848 AC: 1765 AN: 2082

Alfa AF: 0.774 Hom.: 4117

ClinVar

Significance: Benign

Submissions summary: Benign:3

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

Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency Benign:1

Jul 30, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Benign:1

Jan 26, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.58
CADD	Benign	6.3
DANN	Benign	0.84
PhyloP100		0.086
PromoterAI		0.054	Neutral
Mutation Taster		=100/0	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: rs6468; hg19: chr6-32006317; COSMIC: COSV64473789; COSMIC: COSV64473789;