X-71141247-ACAGCAGCAG-ACAG

Position:

chrX-71141247-ACAGCAGCAG-ACAG

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP3BP6BS2

The NM_005120.3(MED12):c.6303_6308delGCAGCA(p.Gln2102_Gln2103del) variant causes a disruptive inframe deletion change. The variant allele was found at a frequency of 0.0000474 in 1,159,380 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 18 hemizygotes in GnomAD. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000064 ( 0 hom., 3 hem., cov: 23)

Exomes 𝑓: 0.000046 ( 0 hom. 15 hem. )

Consequence

MED12
NM_005120.3 disruptive_inframe_deletion

Scores

Not classified

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:2

Conservation

PhyloP100: 3.82

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:

MED12 (HGNC:):

MED12 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP3

Nonframeshift variant in repetitive region in NM_005120.3

BP6

Variant X-71141247-ACAGCAG-A is Benign according to our data. Variant chrX-71141247-ACAGCAG-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 458828.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=2}. Variant chrX-71141247-ACAGCAG-A is described in Lovd as [Likely_benign].

BS2

High Hemizygotes in GnomAd4 at 3 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MED12	NM_005120.3 linkuse as main transcript	c.6303_6308delGCAGCA	p.Gln2102_Gln2103del	disruptive_inframe_deletion	43/45	ENST00000374080.8	NP_005111.2	Q93074-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MED12	ENST00000374080.8 linkuse as main transcript	c.6303_6308delGCAGCA	p.Gln2102_Gln2103del	disruptive_inframe_deletion	43/45	1	NM_005120.3	ENSP00000363193.3		Q93074-1

Frequencies

GnomAD3 genomes

AF:

0.0000636

AC:

AN:

110085

Hom.:

Cov.:

AF XY:

0.0000918

AC XY:

AN XY:

32697

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.000133

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000362

AC:

AN:

110447

Hom.:

AF XY:

0.00

AC XY:

AN XY:

38777

show subpopulations

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 SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000959

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000457

AC:

AN:

1049295

Hom.:

AF XY:

0.0000440

AC XY:

AN XY:

340915

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000564

Gnomad4 OTH exome

AF:

0.0000226

GnomAD4 genome

AF:

0.0000636

AC:

AN:

110085

Hom.:

Cov.:

AF XY:

0.0000918

AC XY:

AN XY:

32697

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000133

Gnomad4 OTH

AF:

0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2024	MED12: BS2 -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 24, 2020	- -

Familial thoracic aortic aneurysm and aortic dissection

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 19, 2016

The c.6303_6308delGCAGCA variant (also known as p.Q2114_Q2115del) is located in coding exon 43 of the MED12 gene. This variant results from an in-frame GCAGCA deletion between nucleotide positions 6303 and 6308. This results in the deletion of two glutamine residues within a poly-glutamine tract. This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. In the ESP, this variant was not observed in 5475 samples with coverage at this position. These amino acid positions range from highly to well conserved on limited sequence alignment. Since supporting evidence is limited at this time, the clinical significance of this variant remains unclear. -

FG syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 02, 2024

This variant, c.6303_6308del, results in the deletion of 2 amino acid(s) of the MED12 protein (p.Gln2114_Gln2115del), but otherwise preserves the integrity of the reading frame. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has not been reported in the literature in individuals affected with MED12-related conditions. ClinVar contains an entry for this variant (Variation ID: 458828). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

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