X-71141271-A-ACAGCAACAGCAGCAG

Variant names:

• chrX-71141271-A-ACAGCAACAGCAGCAG
• rs727503869
• NM_005120.3:c.6321_6335dupGCAGCAGCAACAGCA

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BP3

The NM_005120.3(MED12):​c.6321_6335dupGCAGCAGCAACAGCA​(p.Gln2108_Gln2112dup) variant causes a disruptive inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000956 in 1,046,406 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. It is difficult to determine the true allele frequency of this variant because it is of type INS_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. Q2112Q) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 24)
  • Exomes 𝑓: 9.6e-7 (0 hom. 0 hem.)
• Consequence: MED12 NM_005120.3 disruptive_inframe_insertion
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.99
• 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: Likely_benign. The variant received -1 ACMG points.

• BP3: Nonframeshift variant in repetitive region in NM_005120.3

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.6321_6335dupGCAGCAGCAACAGCA	p.Gln2108_Gln2112dup	disruptive_inframe_insertion	Exon 43 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.6321_6335dupGCAGCAGCAACAGCA	p.Gln2108_Gln2112dup	disruptive_inframe_insertion	Exon 43 of 45	ENSP00000363193.3
	MED12	ENST00000374102.6	TSL:1	c.6330_6344dupGCAGCAGCAACAGCA	p.Gln2111_Gln2115dup	disruptive_inframe_insertion	Exon 43 of 45	ENSP00000363215.2
	MED12	ENST00000690145.1		c.6327_6341dupGCAGCAGCAACAGCA	p.Gln2110_Gln2114dup	disruptive_inframe_insertion	Exon 43 of 45	ENSP00000508818.1

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome AF: 9.56e-7 AC: 1 AN: 1046406 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 338504

African (AFR) AF: 0.00 AC: 0 AN: 24754

American (AMR) AF: 0.00 AC: 0 AN: 27894

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18579

East Asian (EAS) AF: 0.0000369 AC: 1 AN: 27093

South Asian (SAS) AF: 0.00 AC: 0 AN: 49724

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 37640

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4037

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 812594

Other (OTH) AF: 0.00 AC: 0 AN: 44091

GnomAD4 genome Cov.: 24

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		3.0
Mutation Taster		=78/22	polymorphism

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs727503869; hg19: chrX-70361121;