NM_000500.9:c.719T>A

Variant names:

• chr6-32039816-T-A
• rs6476
• NM_000500.9:c.719T>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 7P and 9B. PS3 PM1 PP2 BP4_Strong BP6 BS2

The NM_000500.9(CYP21A2):​c.719T>A​(p.Met240Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000878 in 1,613,904 control chromosomes in the GnomAD database, including 14 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). ClinVar reports functional evidence for this variant: "SCV002598644: Experimental evidence evaluating an impact on protein function demonstrated this complex variant has no detectable enzymatic activity (Tusie-Luna_1990, Higashi_1991, Felix-Lopez_2003, Robins_2005).". Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M240T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0047 (8 hom., cov: 31)
  • Exomes 𝑓: 0.00048 (6 hom.)
• Consequence: CYP21A2 NM_000500.9 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:3 B:3
• Conservation: PhyloP100: 0.343
• Publications: 41 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: Labcorp Genetics (formerly Invitae), Myriad Women’s Health, 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 -2 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV002598644: Experimental evidence evaluating an impact on protein function demonstrated this complex variant has no detectable enzymatic activity (Tusie-Luna_1990, Higashi_1991, Felix-Lopez_2003, Robins_2005).
• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 2 uncertain in NM_000500.9
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 52 curated pathogenic missense variants (we use a threshold of 10). The gene has 5 curated benign missense variants. Trascript score misZ: 1.8021 (below the threshold of 3.09). GenCC associations: The gene is linked to classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency, simple virilizing form, classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency, classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency, salt wasting form.
• BP4: Computational evidence support a benign effect (MetaRNN=0.054983348).
• BP6: Variant 6-32039816-T-A is Benign according to our data. Variant chr6-32039816-T-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 242688.
• BS2: High Homozygotes in GnomAd4 at 8 AR gene

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CYP21A2	NM_000500.9	MANE Select	c.719T>A	p.Met240Lys	missense	Exon 6 of 10	NP_000491.4
	CYP21A2	NM_001128590.4		c.629T>A	p.Met210Lys	missense	Exon 5 of 9	NP_001122062.3	P08686-2
	CYP21A2	NM_001368143.2		c.314T>A	p.Met105Lys	missense	Exon 6 of 10	NP_001355072.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CYP21A2	ENST00000644719.2	MANE Select	c.719T>A	p.Met240Lys	missense	Exon 6 of 10	ENSP00000496625.1	P08686-1
	CYP21A2	ENST00000960600.1		c.719T>A	p.Met240Lys	missense	Exon 6 of 10	ENSP00000630659.1
	CYP21A2	ENST00000960597.1		c.719T>A	p.Met240Lys	missense	Exon 6 of 10	ENSP00000630656.1

Frequencies

GnomAD3 genomes AF: 0.00465 AC: 707 AN: 152162 Hom.: 8 Cov.: 31

Gnomad AFR AF: 0.0158

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00190

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000132

Gnomad OTH AF: 0.00574

GnomAD2 exomes AF: 0.000995 AC: 249 AN: 250242 AF XY: 0.000680

Gnomad AFR exome AF: 0.0128

Gnomad AMR exome AF: 0.000840

Gnomad ASJ exome AF: 0.0000995

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000796

Gnomad OTH exome AF: 0.000327

GnomAD4 exome AF: 0.000481 AC: 703 AN: 1461624 Hom.: 6 Cov.: 54 AF XY: 0.000413 AC XY: 300 AN XY: 727064

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0141 AC: 471 AN: 33462

American (AMR) AF: 0.00132 AC: 59 AN: 44708

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26132

East Asian (EAS) AF: 0.000101 AC: 4 AN: 39692

South Asian (SAS) AF: 0.000104 AC: 9 AN: 86198

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53404

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5766

European-Non Finnish (NFE) AF: 0.0000818 AC: 91 AN: 1111874

Other (OTH) AF: 0.00108 AC: 65 AN: 60388

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.00469 AC: 714 AN: 152280 Hom.: 8 Cov.: 31 AF XY: 0.00447 AC XY: 333 AN XY: 74472

African (AFR) AF: 0.0160 AC: 663 AN: 41542

American (AMR) AF: 0.00190 AC: 29 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5172

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

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

European-Non Finnish (NFE) AF: 0.000132 AC: 9 AN: 68024

Other (OTH) AF: 0.00568 AC: 12 AN: 2114

Alfa AF: 0.000306 Hom.: 0

ESP6500AA AF: 0.0182 AC: 80

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00137 AC: 166

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	2	ADRENAL HYPERPLASIA, CONGENITAL, DUE TO 21-HYDROXYLASE DEFICIENCY (3)
1	1	1	not provided (3)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.072
BayesDel_addAF	Benign	-0.45	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	11
DANN	Benign	0.88
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.0012	N
MetaRNN	Benign	0.055	T
MetaSVM	Benign	-1.1	T
PhyloP100		0.34
PrimateAI	Benign	0.30	T
PROVEAN	Benign	2.8	N
REVEL	Benign	0.18
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.14
MVP		0.76
MPC		0.72
ClinPred		0.0032	T
GERP RS		1.6
gMVP		0.48
Mutation Taster		=98/2	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs6476; hg19: chr6-32007593;