rs1556334331

chrX-71121033-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2 PM5 PP2

The NM_005120.3(MED12):c.616C>G(p.Arg206Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R206Q) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 22)
• Consequence: MED12 NM_005120.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1 O:1
• Conservation: PhyloP100: 0.166

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 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrX-71121034-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 1019021.We mark this variant Likely_pathogenic, oryginal submissions are: {not_provided=1, Likely_pathogenic=1, Uncertain_significance=1}.
• PP2: Missense variant where missense usually causes diseases, MED12

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MED12	NM_005120.3	c.616C>G	p.Arg206Gly	missense_variant	5/45	ENST00000374080.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MED12	ENST00000374080.8	c.616C>G	p.Arg206Gly	missense_variant	5/45	1	NM_005120.3	P4

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 22

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

FG syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jun 28, 2017

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. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C65"). This variant has not been reported in the literature in individuals with MED12-related disease. This variant is not present in population databases (ExAC no frequency). This sequence change replaces arginine with glycine at codon 206 of the MED12 protein (p.Arg206Gly). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and glycine. -

FG syndrome;C0796022:X-linked intellectual disability with marfanoid habitus;C3698541:Blepharophimosis - intellectual disability syndrome, MKB type Other:1

not provided, no classification provided

phenotyping only

GenomeConnect - Invitae Patient Insights Network

-

Variant classified as Uncertain significance and reported on 07-06-2017 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.49
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Uncertain	0.040
Cadd	Benign	20
Dann	Uncertain	1.0
DEOGEN2	Benign	0.067	T;.;T
FATHMM_MKL	Uncertain	0.76	D
LIST_S2	Uncertain	0.90	D;D;D
M_CAP	Pathogenic	0.64	D
MetaRNN	Uncertain	0.66	D;D;D
MetaSVM	Benign	-0.54	T
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.53	T
REVEL	Uncertain	0.31
Sift4G	Uncertain	0.0060	D;D;D
Polyphen		0.99	D;P;P
Vest4		0.44
MutPred		0.61		.;Loss of stability (P = 0.1078);Loss of stability (P = 0.1078);
MVP		0.87
MPC		1.2
ClinPred		0.78	D
GERP RS		3.4
Varity_R		0.59
gMVP		0.67

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

Other links and lift over

dbSNP: rs1556334331; hg19: chrX-70340883;