NM_005120.3:c.4416-60_4416-16delCTTCTCTTCTCTTCTCTTCTCTTCTCTTCTCTTCTCTTCTCTTCT

Variant names:

• chrX-71132767-CCTCTTCTCTTCTCTTCTCTTCTCTTCTCTTCTCTTCTCTTCTCTT-C
• rs56658066
• NM_005120.3:c.4416-60_4416-16delCTTCTCTTCTCTTCTCTTCTCTTCTCTTCTCTTCTCTTCTCTTCT

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.

The NM_005120.3(MED12):​c.4416-60_4416-16delCTTCTCTTCTCTTCTCTTCTCTTCTCTTCTCTTCTCTTCTCTTCT variant causes a intron change involving the alteration of a non-conserved nucleotide. It is difficult to determine the true allele frequency of this variant because it is of type DEL_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.

• Frequency:
  • Genomes: 𝑓 0.000022 (0 hom., 1 hem., cov: 0)
  • Exomes 𝑓: 0.000041 (0 hom. 7 hem.)
  • Failed GnomAD Quality Control
• Consequence: MED12 NM_005120.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.312
• 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: 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MED12	NM_005120.3	c.4416-60_4416-16delCTTCTCTTCTCTTCTCTTCTCTTCTCTTCTCTTCTCTTCTCTTCT		intron_variant	Intron 31 of 44	ENST00000374080.8	NP_005111.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MED12	ENST00000374080.8	c.4416-77_4416-33delCTCTTCTCTTCTCTTCTCTTCTCTTCTCTTCTCTTCTCTTCTCTT		intron_variant	Intron 31 of 44	1	NM_005120.3	ENSP00000363193.3

Frequencies

GnomAD3 genomes AF: 0.0000221 AC: 2 AN: 90626 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.0000407

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000219

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000409 AC: 23 AN: 562803 Hom.: 0 AF XY: 0.0000429 AC XY: 7 AN XY: 163155

African (AFR) AF: 0.0000675 AC: 1 AN: 14814

American (AMR) AF: 0.00 AC: 0 AN: 21585

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 14203

East Asian (EAS) AF: 0.00 AC: 0 AN: 23314

South Asian (SAS) AF: 0.00 AC: 0 AN: 34554

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 33470

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1922

European-Non Finnish (NFE) AF: 0.0000536 AC: 21 AN: 391577

Other (OTH) AF: 0.0000365 AC: 1 AN: 27364

GnomAD4 genome AF: 0.0000221 AC: 2 AN: 90626 Hom.: 0 Cov.: 0 AF XY: 0.0000535 AC XY: 1 AN XY: 18708

African (AFR) AF: 0.0000407 AC: 1 AN: 24570

American (AMR) AF: 0.00 AC: 0 AN: 8062

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2315

East Asian (EAS) AF: 0.00 AC: 0 AN: 2580

South Asian (SAS) AF: 0.00 AC: 0 AN: 1620

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 3833

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 210

European-Non Finnish (NFE) AF: 0.0000219 AC: 1 AN: 45645

Other (OTH) AF: 0.00 AC: 0 AN: 1190

Alfa AF: 0.00 Hom.: 352

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.31

Splicing

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

Other links and lift over

dbSNP: rs56658066; hg19: chrX-70352617;