X-71129320-G-C

Variant names:

• chrX-71129320-G-C
• rs1060504499
• NM_005120.3:c.3582G>C

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.3582G>C​(p.Lys1194Asn) 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. K1194K) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 23)
• Consequence: MED12 NM_005120.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.75
• 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=0.22330847).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MED12	NM_005120.3	c.3582G>C	p.Lys1194Asn	missense_variant	Exon 26 of 45	ENST00000374080.8	NP_005111.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MED12	ENST00000374080.8	c.3582G>C	p.Lys1194Asn	missense_variant	Exon 26 of 45	1	NM_005120.3	ENSP00000363193.3

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 23

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.78
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.064	T;.;T
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.91	D;D;D
M_CAP	Uncertain	0.10	D
MetaRNN	Benign	0.22	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.4	.;L;L
PhyloP100		1.8
PrimateAI	Uncertain	0.79	T
PROVEAN	Uncertain	-2.5	D;N;N
REVEL	Benign	0.090
Sift	Uncertain	0.010	D;T;T
Sift4G	Uncertain	0.027	D;D;D
Polyphen		0.32	B;B;D
Vest4		0.53
MutPred		0.29		.;Loss of ubiquitination at K1194 (P = 0.003);Loss of ubiquitination at K1194 (P = 0.003);
MVP		0.84
MPC		1.8
ClinPred		0.92	D
GERP RS		2.2
PromoterAI		-0.025	Neutral
Varity_R		0.45
gMVP		0.73
Mutation Taster		=71/29	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs1060504499; hg19: chrX-70349170;