X-71140797-ACAG-ACAGCAGCAG

Variant names:

• chrX-71140797-A-ACAGCAG
• rs757160341
• NM_005120.3:c.6223_6228dupCAGCAG

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.6223_6228dupCAGCAG​(p.Gln2075_Gln2076dup) variant causes a conservative inframe insertion change. The variant allele was found at a frequency of 0.000182 in 109,909 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 3 hemizygotes in GnomAD. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00018 (0 hom., 3 hem., cov: 22)
  • Exomes 𝑓: 0.00030 (0 hom. 57 hem.)
  • Failed GnomAD Quality Control
• Consequence: MED12 NM_005120.3 conservative_inframe_insertion
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:4
• Conservation: PhyloP100: 4.36
• Publications: 4 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-71140797-A-ACAGCAG is Benign according to our data. Variant chrX-71140797-A-ACAGCAG is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 213619.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000182 (20/109909) while in subpopulation NFE AF = 0.000343 (18/52464). AF 95% confidence interval is 0.000222. 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MED12	NM_005120.3	MANE Select	c.6223_6228dupCAGCAG	p.Gln2075_Gln2076dup	conservative_inframe_insertion	Exon 42 of 45	NP_005111.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MED12	ENST00000374080.8	TSL:1 MANE Select	c.6223_6228dupCAGCAG	p.Gln2075_Gln2076dup	conservative_inframe_insertion	Exon 42 of 45	ENSP00000363193.3
	MED12	ENST00000374102.6	TSL:1	c.6232_6237dupCAGCAG	p.Gln2078_Gln2079dup	conservative_inframe_insertion	Exon 42 of 45	ENSP00000363215.2
	MED12	ENST00000938012.1		c.6265_6270dupCAGCAG	p.Gln2089_Gln2090dup	conservative_inframe_insertion	Exon 42 of 45	ENSP00000608071.1

Frequencies

GnomAD3 genomes AF: 0.000182 AC: 20 AN: 109909 Hom.: 0 Cov.: 22

Gnomad AFR AF: 0.0000662

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: 0.000343

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000190 AC: 32 AN: 168423 AF XY: 0.000101

Gnomad AFR exome AF: 0.0000853

Gnomad AMR exome AF: 0.0000762

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000773

Gnomad FIN exome AF: 0.0000740

Gnomad NFE exome AF: 0.000335

Gnomad OTH exome AF: 0.000473

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.000305 AC: 333 AN: 1091813 Hom.: 0 Cov.: 33 AF XY: 0.000159 AC XY: 57 AN XY: 359025

African (AFR) AF: 0.000152 AC: 4 AN: 26292

American (AMR) AF: 0.0000570 AC: 2 AN: 35090

Ashkenazi Jewish (ASJ) AF: 0.0000519 AC: 1 AN: 19274

East Asian (EAS) AF: 0.0000664 AC: 2 AN: 30106

South Asian (SAS) AF: 0.00 AC: 0 AN: 53834

European-Finnish (FIN) AF: 0.0000509 AC: 2 AN: 39297

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4117

European-Non Finnish (NFE) AF: 0.000376 AC: 315 AN: 837965

Other (OTH) AF: 0.000153 AC: 7 AN: 45838

GnomAD4 genome AF: 0.000182 AC: 20 AN: 109909 Hom.: 0 Cov.: 22 AF XY: 0.0000923 AC XY: 3 AN XY: 32501

African (AFR) AF: 0.0000662 AC: 2 AN: 30218

American (AMR) AF: 0.00 AC: 0 AN: 10275

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2618

East Asian (EAS) AF: 0.00 AC: 0 AN: 3492

South Asian (SAS) AF: 0.00 AC: 0 AN: 2585

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5889

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 225

European-Non Finnish (NFE) AF: 0.000343 AC: 18 AN: 52464

Other (OTH) AF: 0.00 AC: 0 AN: 1465

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	1	not specified (2)
-	-	1	Familial thoracic aortic aneurysm and aortic dissection (1)
-	-	1	FG syndrome (1)
-	1	-	History of neurodevelopmental disorder (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		4.4
Mutation Taster		=82/18	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs757160341; hg19: chrX-70360647; COSMIC: COSV105882314;