chrX-71141301-A-C

Variant names:

• chrX-71141301-A-C
• rs757508922
• NM_005120.3:c.6339A>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.6339A>C​(p.Gln2113His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000475 in 1,053,121 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. 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. Synonymous variant affecting the same amino acid position (i.e. Q2113Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 24)
  • Exomes 𝑓: 0.0000047 (0 hom. 1 hem.)
• Consequence: MED12 NM_005120.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.00500
• 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=0.25643474).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MED12	NM_005120.3	c.6339A>C	p.Gln2113His	missense_variant	Exon 43 of 45	ENST00000374080.8	NP_005111.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MED12	ENST00000374080.8	c.6339A>C	p.Gln2113His	missense_variant	Exon 43 of 45	1	NM_005120.3	ENSP00000363193.3

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD2 exomes AF: 0.00000879 AC: 1 AN: 113704 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000232

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000475 AC: 5 AN: 1053121 Hom.: 0 Cov.: 33 AF XY: 0.00000291 AC XY: 1 AN XY: 344041

African (AFR) AF: 0.00 AC: 0 AN: 24896

American (AMR) AF: 0.00 AC: 0 AN: 27911

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18633

East Asian (EAS) AF: 0.00 AC: 0 AN: 27132

South Asian (SAS) AF: 0.00 AC: 0 AN: 49858

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 37650

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4080

European-Non Finnish (NFE) AF: 0.00000611 AC: 5 AN: 818601

Other (OTH) AF: 0.00 AC: 0 AN: 44360

GnomAD4 genome Cov.: 24

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.26
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.58
CADD	Benign	4.4
DANN	Benign	0.77
DEOGEN2	Benign	0.065	T;.;T
FATHMM_MKL	Benign	0.30	N
LIST_S2	Benign	0.73	T;T;T
M_CAP	Uncertain	0.16	D
MetaRNN	Benign	0.26	T;T;T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	0.81	.;.;L
PhyloP100		-0.0050
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-1.4	.;N;N
REVEL	Benign	0.22
Sift	Pathogenic	0.0	.;D;D
Sift4G	Uncertain	0.0080	D;T;T
Polyphen		0.94	P;D;P
Vest4		0.36
MutPred		0.29		.;.;Loss of solvent accessibility (P = 0.0635);
MVP		0.34
MPC		0.66
ClinPred		0.43	T
GERP RS		-3.6
Varity_R		0.26
gMVP		0.51
Mutation Taster		=94/6	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: rs757508922; hg19: chrX-70361151;