X-71140829-GGCAGCAGCA-GGCAGCA

Variant names:

• chrX-71140829-GGCA-G
• rs786200971
• NM_005120.3:c.6256_6258delCAG

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP3 BP6 BS1 BS2

The NM_005120.3(MED12):​c.6256_6258delCAG​(p.Gln2086del) variant causes a conservative inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000106 in 1,173,953 control chromosomes in the GnomAD database, including 1 homozygotes. There are 20 hemizygotes in GnomAD. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.000075 (0 hom., 3 hem., cov: 22)
  • Exomes 𝑓: 0.00011 (1 hom. 17 hem.)
• Consequence: MED12 NM_005120.3 conservative_inframe_deletion
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3
• Conservation: PhyloP100: 3.03
• Publications: 1 publications found

Genes affected

MED12 (HGNC:11957): (mediator complex subunit 12) The initiation of transcription is controlled in part by a large protein assembly known as the preinitiation complex. A component of this preinitiation complex is a 1.2 MDa protein aggregate called Mediator. This Mediator component binds with a CDK8 subcomplex which contains the protein encoded by this gene, mediator complex subunit 12 (MED12), along with MED13, CDK8 kinase, and cyclin C. The CDK8 subcomplex modulates Mediator-polymerase II interactions and thereby regulates transcription initiation and reinitation rates. The MED12 protein is essential for activating CDK8 kinase. Defects in this gene cause X-linked Opitz-Kaveggia syndrome, also known as FG syndrome, and Lujan-Fryns syndrome. [provided by RefSeq, Aug 2009]

MED12 Gene-Disease associations (from GenCC):

• FG syndrome 1

  Inheritance: XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), G2P, Orphanet
• MED12-related intellectual disability syndrome

  Inheritance: XL Classification: DEFINITIVE Submitted by: ClinGen
• X-linked intellectual disability with marfanoid habitus

  Inheritance: XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), G2P, Orphanet
• blepharophimosis - intellectual disability syndrome, MKB type

  Inheritance: XL Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet
• cholestasis-pigmentary retinopathy-cleft palate syndrome

  Inheritance: XL Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)

ENSG00000228427 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -10 ACMG points.

• BP3: Nonframeshift variant in repetitive region in NM_005120.3
• BP6: Variant X-71140829-GGCA-G is Benign according to our data. Variant chrX-71140829-GGCA-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 213650.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0000753 (8/106303) while in subpopulation AFR AF = 0.000103 (3/29104). AF 95% confidence interval is 0.000038. There are 0 homozygotes in GnomAd4. There are 3 alleles in the male GnomAd4 subpopulation. Median coverage is 22. This position passed quality control check.
• BS2: High Hemizygotes in GnomAd4 at 3 XL gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005120.3. 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
	MED12	NM_005120.3	MANE Select	c.6256_6258delCAG	p.Gln2086del	conservative_inframe_deletion	Exon 42 of 45	NP_005111.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MED12	ENST00000374080.8	TSL:1 MANE Select	c.6256_6258delCAG	p.Gln2086del	conservative_inframe_deletion	Exon 42 of 45	ENSP00000363193.3
	MED12	ENST00000374102.6	TSL:1	c.6265_6267delCAG	p.Gln2089del	conservative_inframe_deletion	Exon 42 of 45	ENSP00000363215.2
	MED12	ENST00000938012.1		c.6298_6300delCAG	p.Gln2100del	conservative_inframe_deletion	Exon 42 of 45	ENSP00000608071.1

Frequencies

GnomAD3 genomes AF: 0.0000753 AC: 8 AN: 106303 Hom.: 0 Cov.: 22

Gnomad AFR AF: 0.000103

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000975

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000215 AC: 34 AN: 158393 AF XY: 0.0000364

Gnomad AFR exome AF: 0.000184

Gnomad AMR exome AF: 0.0000401

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00101

Gnomad NFE exome AF: 0.000255

Gnomad OTH exome AF: 0.000249

GnomAD4 exome AF: 0.000110 AC: 117 AN: 1067650 Hom.: 1 AF XY: 0.0000491 AC XY: 17 AN XY: 346398

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

African (AFR) AF: 0.00 AC: 0 AN: 25811

American (AMR) AF: 0.00 AC: 0 AN: 34237

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18776

East Asian (EAS) AF: 0.00 AC: 0 AN: 29446

South Asian (SAS) AF: 0.00 AC: 0 AN: 51942

European-Finnish (FIN) AF: 0.00112 AC: 41 AN: 36550

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4053

European-Non Finnish (NFE) AF: 0.0000888 AC: 73 AN: 822011

Other (OTH) AF: 0.0000669 AC: 3 AN: 44824

⚠️ 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: 0.0000753 AC: 8 AN: 106303 Hom.: 0 Cov.: 22 AF XY: 0.0000999 AC XY: 3 AN XY: 30037

African (AFR) AF: 0.000103 AC: 3 AN: 29104

American (AMR) AF: 0.00 AC: 0 AN: 9865

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2581

East Asian (EAS) AF: 0.00 AC: 0 AN: 3243

South Asian (SAS) AF: 0.00 AC: 0 AN: 2409

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5566

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 195

European-Non Finnish (NFE) AF: 0.0000975 AC: 5 AN: 51296

Other (OTH) AF: 0.00 AC: 0 AN: 1389

Alfa AF: 0.00603 Hom.: 0

Asia WGS AF: 0.00279 AC: 7 AN: 2522

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	1	Familial thoracic aortic aneurysm and aortic dissection (1)
-	1	-	FG syndrome (1)
-	-	1	MED12-related disorder (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		3.0
Mutation Taster		=79/21	polymorphism

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: rs786200971; hg19: chrX-70360679; COSMIC: COSV61333332; COSMIC: COSV61333332;