rs766775649

Variant names:

• chrX-71141247-ACAGCAGCAG-A
• rs766775649
• NM_005120.3:c.6300_6308delGCAGCAGCA

Your query was ambiguous. Multiple possible variants found:

• chrX-71141247-ACAGCAGCAG-A
• chrX-71141247-ACAGCAGCAG-ACAG
• chrX-71141247-ACAGCAGCAG-ACAGCAG
• chrX-71141247-ACAGCAGCAG-ACAGCAGCAGCAG
• chrX-71141247-ACAGCAGCAG-ACAGCAGCAGCAGCAG
• chrX-71141247-ACAGCAGCAG-ACAGCAGCAGCAGCAGCAG
• chrX-71141247-ACAGCAGCAG-ACAGCAGCAGCAGCAGCAGCAG

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP3

The NM_005120.3(MED12):​c.6300_6308delGCAGCAGCA​(p.Gln2101_Gln2103del) variant causes a disruptive inframe deletion change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. Q2100Q) 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_deletion
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.44
• Publications: 3 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)

ENSG00000228427 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• 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.6300_6308delGCAGCAGCA	p.Gln2101_Gln2103del	disruptive_inframe_deletion	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.6300_6308delGCAGCAGCA	p.Gln2101_Gln2103del	disruptive_inframe_deletion	Exon 43 of 45	ENSP00000363193.3	Q93074-1
	MED12	ENST00000374102.6	TSL:1	c.6309_6317delGCAGCAGCA	p.Gln2104_Gln2106del	disruptive_inframe_deletion	Exon 43 of 45	ENSP00000363215.2	Q93074-2
	MED12	ENST00000938012.1		c.6342_6350delGCAGCAGCA	p.Gln2115_Gln2117del	disruptive_inframe_deletion	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: 1049299 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 340919

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: 815518

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

GnomAD4 genome Cov.: 23

Alfa AF: 0.00 Hom.: 0

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		4.4
Mutation Taster		=139/61	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs766775649; hg19: chrX-70361097;