X-71132767-CCTCTTCTCTTCTCTTCTCTTCTCTTCTCTTCTCTTCTCTTCTCTT-CCTCTTCTCTT

Variant names:

• chrX-71132767-CCTCTTCTCTTCTCTTCTCTTCTCTTCTCTTCTCTT-C
• rs56658066
• NM_005120.3:c.4416-50_4416-16delCTTCTCTTCTCTTCTCTTCTCTTCTCTTCTCTTCT

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BS1 BS2

The NM_005120.3(MED12):​c.4416-50_4416-16delCTTCTCTTCTCTTCTCTTCTCTTCTCTTCTCTTCT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00488 in 653,256 control chromosomes in the GnomAD database, including 12 homozygotes. There are 1,013 hemizygotes in GnomAD. 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 0.0052 (2 hom., 116 hem., cov: 0)
  • Exomes 𝑓: 0.0048 (10 hom. 897 hem.)
• 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: Benign. The variant received -8 ACMG points.

• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00516 (468/90666) while in subpopulation NFE AF = 0.00774 (353/45636). AF 95% confidence interval is 0.00707. There are 2 homozygotes in GnomAd4. There are 116 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 2 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MED12	NM_005120.3	c.4416-50_4416-16delCTTCTCTTCTCTTCTCTTCTCTTCTCTTCTCTTCT		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_4416-43delCTCTTCTCTTCTCTTCTCTTCTCTTCTCTTCTCTT		intron_variant	Intron 31 of 44	1	NM_005120.3	ENSP00000363193.3

Frequencies

GnomAD3 genomes AF: 0.00516 AC: 468 AN: 90626 Hom.: 2 Cov.: 0

Gnomad AFR AF: 0.00151

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00385

Gnomad ASJ AF: 0.00130

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00247

Gnomad FIN AF: 0.00835

Gnomad MID AF: 0.00476

Gnomad NFE AF: 0.00773

Gnomad OTH AF: 0.00588

GnomAD4 exome AF: 0.00483 AC: 2717 AN: 562590 Hom.: 10 AF XY: 0.00550 AC XY: 897 AN XY: 162968

African (AFR) AF: 0.000945 AC: 14 AN: 14814

American (AMR) AF: 0.00185 AC: 40 AN: 21576

Ashkenazi Jewish (ASJ) AF: 0.00113 AC: 16 AN: 14188

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

South Asian (SAS) AF: 0.000984 AC: 34 AN: 34546

European-Finnish (FIN) AF: 0.00487 AC: 163 AN: 33449

Middle Eastern (MID) AF: 0.00469 AC: 9 AN: 1920

European-Non Finnish (NFE) AF: 0.00590 AC: 2308 AN: 391426

Other (OTH) AF: 0.00486 AC: 133 AN: 27357

GnomAD4 genome AF: 0.00516 AC: 468 AN: 90666 Hom.: 2 Cov.: 0 AF XY: 0.00619 AC XY: 116 AN XY: 18748

African (AFR) AF: 0.00150 AC: 37 AN: 24625

American (AMR) AF: 0.00384 AC: 31 AN: 8076

Ashkenazi Jewish (ASJ) AF: 0.00130 AC: 3 AN: 2315

East Asian (EAS) AF: 0.00 AC: 0 AN: 2570

South Asian (SAS) AF: 0.00248 AC: 4 AN: 1610

European-Finnish (FIN) AF: 0.00835 AC: 32 AN: 3834

Middle Eastern (MID) AF: 0.00529 AC: 1 AN: 189

European-Non Finnish (NFE) AF: 0.00774 AC: 353 AN: 45636

Other (OTH) AF: 0.00579 AC: 7 AN: 1210

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
Mutation Taster		=100/0	polymorphism

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;