rs6477

Variant names:

• chr6-32040013-C-G
• rs6477
• NM_000500.9:c.747C>G

Your query was ambiguous. Multiple possible variants found:

• chr6-32040013-C-G
• chr6-32040013-C-T

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_000500.9(CYP21A2):​c.747C>G​(p.Leu249Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0843 in 1,424,980 control chromosomes in the GnomAD database, including 16,252 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.17 (2057 hom., cov: 31)
  • Exomes 𝑓: 0.075 (14195 hom.)
• Consequence: CYP21A2 NM_000500.9 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.0220
• Publications: 9 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: Benign. The variant received -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.48).
• BP6: Variant 6-32040013-C-G is Benign according to our data. Variant chr6-32040013-C-G is described in ClinVar as Benign. ClinVar VariationId is 256300.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.022 with no splicing effect.
• BS2: High Homozygotes in GnomAd4 at 2057 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.747C>G	p.Leu249Leu	synonymous	Exon 7 of 10	NP_000491.4
	CYP21A2	NM_001128590.4		c.657C>G	p.Leu219Leu	synonymous	Exon 6 of 9	NP_001122062.3	P08686-2
	CYP21A2	NM_001368143.2		c.342C>G	p.Leu114Leu	synonymous	Exon 7 of 10	NP_001355072.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CYP21A2	ENST00000644719.2	MANE Select	c.747C>G	p.Leu249Leu	synonymous	Exon 7 of 10	ENSP00000496625.1	P08686-1
	CYP21A2	ENST00000960600.1		c.783C>G	p.Leu261Leu	synonymous	Exon 7 of 10	ENSP00000630659.1
	CYP21A2	ENST00000960597.1		c.756C>G	p.Leu252Leu	synonymous	Exon 7 of 10	ENSP00000630656.1

Frequencies

GnomAD3 genomes AF: 0.167 AC: 24259 AN: 145264 Hom.: 2054 Cov.: 31

Gnomad AFR AF: 0.214

Gnomad AMI AF: 0.151

Gnomad AMR AF: 0.159

Gnomad ASJ AF: 0.151

Gnomad EAS AF: 0.190

Gnomad SAS AF: 0.257

Gnomad FIN AF: 0.196

Gnomad MID AF: 0.234

Gnomad NFE AF: 0.129

Gnomad OTH AF: 0.182

GnomAD2 exomes AF: 0.125 AC: 26859 AN: 215192 AF XY: 0.124

Gnomad AFR exome AF: 0.176

Gnomad AMR exome AF: 0.131

Gnomad ASJ exome AF: 0.0923

Gnomad EAS exome AF: 0.170

Gnomad FIN exome AF: 0.154

Gnomad NFE exome AF: 0.0890

Gnomad OTH exome AF: 0.119

GnomAD4 exome AF: 0.0749 AC: 95820 AN: 1279602 Hom.: 14195 Cov.: 69 AF XY: 0.0793 AC XY: 50561 AN XY: 637396

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

African (AFR) AF: 0.134 AC: 3670 AN: 27442

American (AMR) AF: 0.0979 AC: 3778 AN: 38610

Ashkenazi Jewish (ASJ) AF: 0.106 AC: 2375 AN: 22460

East Asian (EAS) AF: 0.209 AC: 7515 AN: 35896

South Asian (SAS) AF: 0.197 AC: 14551 AN: 73852

European-Finnish (FIN) AF: 0.170 AC: 8452 AN: 49860

Middle Eastern (MID) AF: 0.132 AC: 586 AN: 4454

European-Non Finnish (NFE) AF: 0.0512 AC: 49889 AN: 973590

Other (OTH) AF: 0.0936 AC: 5004 AN: 53438

⚠️ 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: 0.167 AC: 24262 AN: 145378 Hom.: 2057 Cov.: 31 AF XY: 0.170 AC XY: 12076 AN XY: 71008

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

African (AFR) AF: 0.214 AC: 8328 AN: 38986

American (AMR) AF: 0.158 AC: 2286 AN: 14446

Ashkenazi Jewish (ASJ) AF: 0.151 AC: 472 AN: 3130

East Asian (EAS) AF: 0.190 AC: 917 AN: 4814

South Asian (SAS) AF: 0.256 AC: 1154 AN: 4508

European-Finnish (FIN) AF: 0.196 AC: 2028 AN: 10338

Middle Eastern (MID) AF: 0.227 AC: 58 AN: 256

European-Non Finnish (NFE) AF: 0.129 AC: 8531 AN: 66056

Other (OTH) AF: 0.181 AC: 352 AN: 1942

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.0968 Hom.: 144

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not specified (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.48
CADD	Benign	9.3
DANN	Benign	0.86
PhyloP100		0.022
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs6477; hg19: chr6-32007790; COSMIC: COSV64474341; COSMIC: COSV64474341;