X-71140829-GGCAGCAGCA-GGCAGCA

Variant names:

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP3BP6BS1BS2

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

Scores

Not classified

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:3

Conservation

PhyloP100: 3.03

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 -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 id is 213650.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Benign=1, Uncertain_significance=1}.

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 male gnomad4 subpopulation. Median coverage is 22. This position pass quality control queck.

BS2

High Hemizygotes in GnomAd4 at 3 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MED12	NM_005120.3 link	c.6256_6258delCAG	p.Gln2086del	conservative_inframe_deletion	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.6256_6258delCAG	p.Gln2086del	conservative_inframe_deletion	Exon 42 of 45	1	NM_005120.3	ENSP00000363193.3		Q93074-1

Frequencies

GnomAD3 genomes

AF:

0.0000753

AC:

AN:

106303

Hom.:

Cov.:

AF XY:

0.0000999

AC XY:

AN XY:

30037

show subpopulations

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

GnomAD4 exome

AF:

0.000110

AC:

117

AN:

1067650

Hom.:

AF XY:

0.0000491

AC XY:

AN XY:

346398

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:

0.00112

Gnomad4 NFE exome

AF:

0.0000888

Gnomad4 OTH exome

AF:

0.0000669

GnomAD4 genome

AF:

0.0000753

AC:

AN:

106303

Hom.:

Cov.:

AF XY:

0.0000999

AC XY:

AN XY:

30037

show subpopulations

Gnomad4 AFR

AF:

0.000103

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:

0.0000975

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.00603

Hom.:

Asia WGS

AF:

0.00279

AC:

AN:

2522

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

FG syndrome

Uncertain:1

Jan 15, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant, c.6256_6258del, results in the deletion of 1 amino acid(s) of the MED12 protein (p.Gln2086del), 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 been observed in individual(s) with clinical features of MED12-related conditions (PMID: 34356170). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 213650). 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. -

Familial thoracic aortic aneurysm and aortic dissection

Benign:1

Oct 25, 2022

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely 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. -

not provided

Benign:1

Nov 12, 2020

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

MED12-related disorder

Benign:1

Dec 22, 2020

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

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

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