rs199873151

Variant names:

• chrX-71124370-C-G
• rs199873151
• 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. The variant received 0 ACMG points: 2P and 2B. PM2 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. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. S652S) has been classified as Likely benign.

• 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
• Publications: 0 publications found

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)

ENSG00000228427 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.10602054).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005120.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MED12	NM_005120.3	MANE Select	c.1956C>G	p.Ser652Arg	missense	Exon 13 of 45	NP_005111.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MED12	ENST00000374080.8	TSL:1 MANE Select	c.1956C>G	p.Ser652Arg	missense	Exon 13 of 45	ENSP00000363193.3
	MED12	ENST00000374102.6	TSL:1	c.1956C>G	p.Ser652Arg	missense	Exon 13 of 45	ENSP00000363215.2
	MED12	ENST00000690145.1		c.1956C>G	p.Ser652Arg	missense	Exon 13 of 45	ENSP00000508818.1

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

African (AFR) AF: 0.00 AC: 0 AN: 26251

American (AMR) AF: 0.00 AC: 0 AN: 34516

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19283

East Asian (EAS) AF: 0.00 AC: 0 AN: 30034

South Asian (SAS) AF: 0.00 AC: 0 AN: 53210

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40088

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4117

European-Non Finnish (NFE) AF: 0.00000120 AC: 1 AN: 835822

Other (OTH) AF: 0.00 AC: 0 AN: 45758

GnomAD4 genome Cov.: 23

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	FG syndrome (1)

Computational scores

Source: dbNSFP v4.9

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
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.89	D
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.11	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.1	L
PhyloP100		0.93
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	-1.6	N
REVEL	Benign	0.060
Sift	Benign	0.40	T
Sift4G	Benign	0.074	T
Polyphen		0.64	P
Vest4		0.24
MutPred		0.19		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
Mutation Taster		=93/7	polymorphism

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

Other links and lift over

dbSNP: rs199873151; hg19: chrX-70344220;