6-32038437-CCTG-CCTGCTG

Variant names:

• chr6-32038437-C-CCTG
• rs61338903
• NM_000500.9:c.29_31dupTGC

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP3 BP6

The NM_000500.9(CYP21A2):​c.29_31dupTGC​(p.Leu10dup) variant causes a disruptive inframe insertion change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Benign (no stars).

• Frequency:
  • Genomes: not found (cov: 24)
  • Exomes 𝑓: 0.0000050 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CYP21A2 NM_000500.9 disruptive_inframe_insertion
• Clinical Significance: Benign no assertion criteria provided B:1 O:1
• Conservation: PhyloP100: 1.41
• Publications: 8 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: Laboratory for Molecular Medicine, Myriad Women's Health, Labcorp Genetics (formerly Invitae)
• 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP3: Nonframeshift variant in repetitive region in NM_000500.9
• BP6: Variant 6-32038437-C-CCTG is Benign according to our data. Variant chr6-32038437-C-CCTG is described in ClinVar as Benign. ClinVar VariationId is 12162.Status of the report is no_assertion_criteria_provided, 0 stars.

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.29_31dupTGC	p.Leu10dup	disruptive_inframe_insertion	Exon 1 of 10	NP_000491.4
	CYP21A2	NM_001128590.4		c.29_31dupTGC	p.Leu10dup	disruptive_inframe_insertion	Exon 1 of 9	NP_001122062.3	P08686-2
	CYP21A2	NM_001368143.2		c.-396_-394dupTGC		5_prime_UTR	Exon 1 of 10	NP_001355072.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CYP21A2	ENST00000644719.2	MANE Select	c.29_31dupTGC	p.Leu10dup	disruptive_inframe_insertion	Exon 1 of 10	ENSP00000496625.1	P08686-1
	CYP21A2	ENST00000960600.1		c.29_31dupTGC	p.Leu10dup	disruptive_inframe_insertion	Exon 1 of 10	ENSP00000630659.1
	CYP21A2	ENST00000960597.1		c.29_31dupTGC	p.Leu10dup	disruptive_inframe_insertion	Exon 1 of 10	ENSP00000630656.1

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD2 exomes AF: 0.0000128 AC: 2 AN: 156350 AF XY: 0.0000119

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000499 AC: 7 AN: 1402506 Hom.: 0 Cov.: 3 AF XY: 0.00000578 AC XY: 4 AN XY: 692462

African (AFR) AF: 0.0000315 AC: 1 AN: 31742

American (AMR) AF: 0.00 AC: 0 AN: 36496

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25224

East Asian (EAS) AF: 0.00 AC: 0 AN: 36514

South Asian (SAS) AF: 0.0000749 AC: 6 AN: 80108

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48510

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5120

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1080696

Other (OTH) AF: 0.00 AC: 0 AN: 58096

GnomAD4 genome Cov.: 24

Alfa AF: 0.00 Hom.: 952

ClinVar

ClinVar submissions

Significance: Benign

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	-	1	21-HYDROXYLASE POLYMORPHISM (1)
-	-	-	ADRENAL HYPERPLASIA, CONGENITAL, DUE TO 21-HYDROXYLASE DEFICIENCY (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.4
Mutation Taster		=78/22	polymorphism

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs61338903;

hg19: chr6-32006214;