GeneBe

rs1556338815

Variant names:

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2PP2BP4_Moderate

The NM_005120.3(MED12):​c.5266C>A​(p.Leu1756Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 22)

Consequence

MED12
NM_005120.3 missense

Scores

17

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.901
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP2
Missense variant in the MED12 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 37 curated pathogenic missense variants (we use a threshold of 10). The gene has 108 curated benign missense variants. Gene score misZ: 6.5797 (above the threshold of 3.09). GenCC associations: The gene is linked to MED12-related intellectual disability syndrome, X-linked intellectual disability with marfanoid habitus, blepharophimosis - intellectual disability syndrome, MKB type, FG syndrome 1, cholestasis-pigmentary retinopathy-cleft palate syndrome.
BP4
Computational evidence support a benign effect (MetaRNN=0.17094526).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
MED12NM_005120.3 linkc.5266C>A p.Leu1756Met missense_variant Exon 37 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.5266C>A p.Leu1756Met missense_variant Exon 37 of 45 1 NM_005120.3 ENSP00000363193.3 Q93074-1

Frequencies

GnomAD3 genomes
Cov.:
22
GnomAD4 exome
Cov.:
33
GnomAD4 genome
Cov.:
22

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.084
BayesDel_addAF
Benign
-0.30
T
BayesDel_noAF
Benign
-0.67
CADD
Benign
18
DANN
Benign
0.96
DEOGEN2
Benign
0.027
T;.;T
FATHMM_MKL
Benign
0.38
N
LIST_S2
Benign
0.80
T;T;T
M_CAP
Benign
0.036
D
MetaRNN
Benign
0.17
T;T;T
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
0.0
.;N;N
PrimateAI
Benign
0.42
T
PROVEAN
Benign
0.12
.;N;N
REVEL
Benign
0.041
Sift
Benign
0.18
.;T;T
Sift4G
Benign
0.15
T;T;T
Polyphen
0.88
P;P;P
Vest4
0.24
MutPred
0.23
.;Gain of relative solvent accessibility (P = 0.09);Gain of relative solvent accessibility (P = 0.09);
MVP
0.63
MPC
0.85
ClinPred
0.23
T
GERP RS
4.2
Varity_R
0.19
gMVP
0.046

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

No publications associated with this variant yet.

Other links and lift over

hg19: chrX-70356371; API