X-71141247-ACAGCAGCAG-ACAGCAGCAGCAGCAGCAGCAG

Variant names:

• chrX-71141247-A-ACAGCAGCAGCAG
• rs766775649
• NM_005120.3:c.6297_6308dupGCAGCAGCAGCA

Variant summary

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

The NM_005120.3(MED12):​c.6297_6308dupGCAGCAGCAGCA​(p.Gln2100_Gln2103dup) variant causes a disruptive inframe insertion change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. Q2103Q) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 9.5e-7 (0 hom. 0 hem.)
  • Failed GnomAD Quality Control
• Consequence: MED12 NM_005120.3 disruptive_inframe_insertion
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.31
• 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: 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)

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MED12	NM_005120.3	MANE Select	c.6297_6308dupGCAGCAGCAGCA	p.Gln2100_Gln2103dup	disruptive_inframe_insertion	Exon 43 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.6297_6308dupGCAGCAGCAGCA	p.Gln2100_Gln2103dup	disruptive_inframe_insertion	Exon 43 of 45	ENSP00000363193.3	Q93074-1
	MED12	ENST00000374102.6	TSL:1	c.6306_6317dupGCAGCAGCAGCA	p.Gln2103_Gln2106dup	disruptive_inframe_insertion	Exon 43 of 45	ENSP00000363215.2	Q93074-2
	MED12	ENST00000938012.1		c.6339_6350dupGCAGCAGCAGCA	p.Gln2114_Gln2117dup	disruptive_inframe_insertion	Exon 43 of 45	ENSP00000608071.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 9.53e-7 AC: 1 AN: 1049302 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 340922

African (AFR) AF: 0.00 AC: 0 AN: 24797

American (AMR) AF: 0.00 AC: 0 AN: 27872

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18586

East Asian (EAS) AF: 0.00 AC: 0 AN: 27037

South Asian (SAS) AF: 0.00 AC: 0 AN: 49740

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 37570

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3997

European-Non Finnish (NFE) AF: 0.00000123 AC: 1 AN: 815521

Other (OTH) AF: 0.00 AC: 0 AN: 44182

GnomAD4 genome Cov.: 23

ClinVar

ClinVar submissions

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
PhyloP100		2.3

Splicing

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs766775649;

hg19: chrX-70361097;