GeneBe

rs766775649

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP3

The NM_005120.3(MED12):​c.6300_6308delGCAGCAGCA​(p.Gln2101_Gln2103del) variant causes a disruptive inframe deletion change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. Q2100Q) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 23)
Exomes 𝑓: 9.5e-7 ( 0 hom. 0 hem. )
Failed GnomAD Quality Control

Consequence

MED12
NM_005120.3 disruptive_inframe_deletion

Scores

Not classified

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.44

Publications

3 publications found
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 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)

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP3
Nonframeshift variant in repetitive region in NM_005120.3

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
MED12NM_005120.3 linkc.6300_6308delGCAGCAGCA p.Gln2101_Gln2103del disruptive_inframe_deletion Exon 43 of 45 ENST00000374080.8 NP_005111.2 Q93074-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
MED12ENST00000374080.8 linkc.6300_6308delGCAGCAGCA p.Gln2101_Gln2103del disruptive_inframe_deletion Exon 43 of 45 1 NM_005120.3 ENSP00000363193.3 Q93074-1

Frequencies

GnomAD3 genomes
Cov.:
23
GnomAD4 exome
Data not reliable, filtered out with message: AS_VQSR
AF:
9.53e-7
AC:
1
AN:
1049299
Hom.:
0
AF XY:
0.00
AC XY:
0
AN XY:
340919
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
24797
American (AMR)
AF:
0.00
AC:
0
AN:
27872
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
18586
East Asian (EAS)
AF:
0.00
AC:
0
AN:
27037
South Asian (SAS)
AF:
0.00
AC:
0
AN:
49740
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
37570
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
3997
European-Non Finnish (NFE)
AF:
0.00000123
AC:
1
AN:
815518
Other (OTH)
AF:
0.00
AC:
0
AN:
44182
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.475
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
GnomAD4 genome
Cov.:
23
Alfa
AF:
0.00
Hom.:
0

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

FG syndrome Uncertain:1
Dec 04, 2020
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This variant, c.6300_6308del, results in the deletion of 3 amino acid(s) of the MED12 protein (p.Gln2113_Gln2115del), but otherwise preserves the integrity of the reading frame. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with MED12-related conditions. 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
PhyloP100
4.4
Mutation Taster
=139/61
polymorphism

Splicing

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

Publications

Other links and lift over

dbSNP: rs766775649; hg19: chrX-70361097; API