chrX-71118787-C-G

Variant names:

• chrX-71118787-C-G
• rs1018272698
• NM_005120.3:c.33C>G

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.33C>G​(p.His11Gln) 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. 14/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Synonymous variant affecting the same amino acid position (i.e. H11H) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 20)
• Consequence: MED12 NM_005120.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.40
• 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: G2P, Labcorp Genetics (formerly Invitae), 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: Orphanet, Labcorp Genetics (formerly Invitae), G2P
• blepharophimosis - intellectual disability syndrome, MKB type

  Inheritance: XL Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae)
• cholestasis-pigmentary retinopathy-cleft palate syndrome

  Inheritance: XL Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)

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=0.12242848).

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MED12	NM_005120.3	MANE Select	c.33C>G	p.His11Gln	missense	Exon 1 of 45	NP_005111.2	Q93074-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MED12	ENST00000374080.8	TSL:1 MANE Select	c.33C>G	p.His11Gln	missense	Exon 1 of 45	ENSP00000363193.3	Q93074-1
	MED12	ENST00000374102.6	TSL:1	c.33C>G	p.His11Gln	missense	Exon 1 of 45	ENSP00000363215.2	Q93074-2
	MED12	ENST00000938012.1		c.33C>G	p.His11Gln	missense	Exon 1 of 45	ENSP00000608071.1

Frequencies

GnomAD3 genomes Cov.: 20

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 20

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.25
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	22
DANN	Benign	0.94
DEOGEN2	Benign	0.30	T
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Benign	0.66	T
M_CAP	Pathogenic	0.72	D
MetaRNN	Benign	0.12	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-1.1	N
PhyloP100		3.4
PrimateAI	Pathogenic	0.83	D
PROVEAN	Benign	-0.28	N
REVEL	Benign	0.15
Sift	Benign	0.39	T
Sift4G	Benign	1.0	T
Polyphen		0.054	B
Vest4		0.21
MutPred		0.22		Gain of disorder (P = 0.0373)
MVP		0.54
MPC		1.0
ClinPred		0.78	D
GERP RS		4.1
PromoterAI		0.071	Neutral
Varity_R		0.33
gMVP		0.78
Mutation Taster		=78/22	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: rs1018272698; hg19: chrX-70338637;