X-71140797-ACAG-ACAGCAG

Variant names:

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP3BP6_Very_StrongBS1BS2

The NM_005120.3(MED12):c.6226_6228dupCAG(p.Gln2076dup) variant causes a conservative inframe insertion change. The variant allele was found at a frequency of 0.000409 in 1,201,713 control chromosomes in the GnomAD database, including 1 homozygotes. There are 100 hemizygotes in GnomAD. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.00046 ( 0 hom., 14 hem., cov: 22)

Exomes 𝑓: 0.00040 ( 1 hom. 86 hem. )

Consequence

MED12
NM_005120.3 conservative_inframe_insertion

Scores

Not classified

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 4.36

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -17 ACMG points.

BP3

Nonframeshift variant in repetitive region in NM_005120.3

BP6

Variant X-71140797-A-ACAG is Benign according to our data. Variant chrX-71140797-A-ACAG is described in ClinVar as [Likely_benign]. Clinvar id is 166875.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.000464 (51/109953) while in subpopulation EAS AF= 0.000575 (2/3480). AF 95% confidence interval is 0.000146. There are 0 homozygotes in gnomad4. There are 14 alleles in male gnomad4 subpopulation. Median coverage is 22. This position pass quality control queck.

BS2

High Hemizygotes in GnomAd4 at 14 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MED12	NM_005120.3 link	c.6226_6228dupCAG	p.Gln2076dup	conservative_inframe_insertion	Exon 42 of 45	ENST00000374080.8	NP_005111.2	Q93074-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MED12	ENST00000374080.8 link	c.6226_6228dupCAG	p.Gln2076dup	conservative_inframe_insertion	Exon 42 of 45	1	NM_005120.3	ENSP00000363193.3		Q93074-1

Frequencies

GnomAD3 genomes

AF:

0.000464

AC:

AN:

109909

Hom.:

Cov.:

AF XY:

0.000431

AC XY:

AN XY:

32501

show subpopulations

Gnomad AFR

AF:

0.0000331

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.0130

Gnomad EAS

AF:

0.000573

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000248

Gnomad OTH

AF:

0.000683

GnomAD3 exomes

AF:

0.000790

AC:

133

AN:

168423

Hom.:

AF XY:

0.000386

AC XY:

AN XY:

59581

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.0129

Gnomad EAS exome

AF:

0.000541

Gnomad SAS exome

AF:

0.000277

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000335

Gnomad OTH exome

AF:

0.000945

GnomAD4 exome

AF:

0.000403

AC:

440

AN:

1091760

Hom.:

Cov.:

AF XY:

0.000240

AC XY:

AN XY:

358968

show subpopulations

Gnomad4 AFR exome

AF:

0.0000380

Gnomad4 AMR exome

AF:

0.0000570

Gnomad4 ASJ exome

AF:

0.0116

Gnomad4 EAS exome

AF:

0.0000997

Gnomad4 SAS exome

AF:

0.000130

Gnomad4 FIN exome

AF:

0.0000254

Gnomad4 NFE exome

AF:

0.000174

Gnomad4 OTH exome

AF:

0.00118

GnomAD4 genome

AF:

0.000464

AC:

AN:

109953

Hom.:

Cov.:

AF XY:

0.000430

AC XY:

AN XY:

32555

show subpopulations

Gnomad4 AFR

AF:

0.0000330

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.0130

Gnomad4 EAS

AF:

0.000575

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000248

Gnomad4 OTH

AF:

0.000674

Bravo

AF:

0.000495

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

Apr 18, 2014

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 05, 2014

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Benign:2

Oct 24, 2022

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

See Variant Classification Assertion Criteria. -

Dec 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

MED12: BS2 -

Familial thoracic aortic aneurysm and aortic dissection

Benign:1

May 31, 2017

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

FG syndrome

Benign:1

Jan 29, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

MED12-related disorder

Benign:1

Jan 18, 2022

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over