rs199873151

Variant names:

• chrX-71124370-C-G
• NM_005120.3:c.1956C>G

Your query was ambiguous. Multiple possible variants found:

• chrX-71124370-C-G
• chrX-71124370-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_005120.3(MED12):​c.1956C>G​(p.Ser652Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000918 in 1,089,079 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 9.2e-7 (0 hom. 0 hem.)
• Consequence: MED12 NM_005120.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.933

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]

ACMG classification

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=0.10602054).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MED12	NM_005120.3	c.1956C>G	p.Ser652Arg	missense_variant	Exon 13 of 45	ENST00000374080.8	NP_005111.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MED12	ENST00000374080.8	c.1956C>G	p.Ser652Arg	missense_variant	Exon 13 of 45	1	NM_005120.3	ENSP00000363193.3

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome AF: 9.18e-7 AC: 1 AN: 1089079 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 355079

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: 0.00000120

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 23

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

FG syndrome Uncertain:1

Oct 08, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces serine, which is neutral and polar, with arginine, which is basic and polar, at codon 652 of the MED12 protein (p.Ser652Arg). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with MED12-related conditions. Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt MED12 protein function with a negative predictive value of 95%. 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
AlphaMissense	Uncertain	0.34
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.61
CADD	Benign	21
DANN	Uncertain	0.98
DEOGEN2	Benign	0.050	T;.;T
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.89	D;D;D
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.11	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.1	.;L;L
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	-1.6	.;N;N
REVEL	Benign	0.060
Sift	Benign	0.40	.;T;T
Sift4G	Benign	0.074	T;T;T
Polyphen		0.64	P;B;B
Vest4		0.24
MutPred		0.19		.;Loss of phosphorylation at S652 (P = 0.0017);Loss of phosphorylation at S652 (P = 0.0017);
MVP		0.38
MPC		1.2
ClinPred		0.53	D
GERP RS		2.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.62
gMVP		0.32

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-70344220;