X-71132767-CCTCTTCTCTTCTCTTCTCTTCTCTTCTCTTCTCTTCTCTTCTCTT-CCTCTTCTCTTCTCTTCTCTTCTCTTCTCTTCTCTTCTCTTCTCTTCTCTTCTCTTCTCTTCTCTTCTCTTCTCTT

Variant names:

• chrX-71132767-C-CCTCTTCTCTTCTCTTCTCTTCTCTTCTCTT
• rs56658066
• NM_005120.3:c.4416-45_4416-16dupCTTCTCTTCTCTTCTCTTCTCTTCTCTTCT

Variant summary

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

The NM_005120.3(MED12):​c.4416-45_4416-16dupCTTCTCTTCTCTTCTCTTCTCTTCTCTTCT 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 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.

• Frequency:
  • Genomes: 𝑓 0.0012 (0 hom., 10 hem., cov: 0)
  • Exomes 𝑓: 0.0011 (4 hom. 210 hem.)
  • Failed GnomAD Quality Control
• Consequence: MED12 NM_005120.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.294
• 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 = 0.0012 (109/90665) while in subpopulation NFE AF = 0.00193 (88/45637). AF 95% confidence interval is 0.0016. There are 0 homozygotes in GnomAd4. There are 10 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.
• BS2: High Hemizygotes in GnomAd4 at 10 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MED12	NM_005120.3	c.4416-45_4416-16dupCTTCTCTTCTCTTCTCTTCTCTTCTCTTCT		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.4416-78_4416-77insCTCTTCTCTTCTCTTCTCTTCTCTTCTCTT		intron_variant	Intron 31 of 44	1	NM_005120.3	ENSP00000363193.3

Frequencies

GnomAD3 genomes AF: 0.00120 AC: 109 AN: 90625 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.000326

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00124

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000388

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00193

Gnomad OTH AF: 0.00168

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00109 AC: 616 AN: 562729 Hom.: 4 AF XY: 0.00129 AC XY: 210 AN XY: 163131

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.000675 AC: 10 AN: 14812

American (AMR) AF: 0.00190 AC: 41 AN: 21578

Ashkenazi Jewish (ASJ) AF: 0.0000704 AC: 1 AN: 14203

East Asian (EAS) AF: 0.000472 AC: 11 AN: 23314

South Asian (SAS) AF: 0.000608 AC: 21 AN: 34550

European-Finnish (FIN) AF: 0.000687 AC: 23 AN: 33464

Middle Eastern (MID) AF: 0.000520 AC: 1 AN: 1922

European-Non Finnish (NFE) AF: 0.00121 AC: 474 AN: 391522

Other (OTH) AF: 0.00124 AC: 34 AN: 27364

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.00120 AC: 109 AN: 90665 Hom.: 0 Cov.: 0 AF XY: 0.000533 AC XY: 10 AN XY: 18749

African (AFR) AF: 0.000325 AC: 8 AN: 24625

American (AMR) AF: 0.00124 AC: 10 AN: 8074

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

East Asian (EAS) AF: 0.000389 AC: 1 AN: 2570

South Asian (SAS) AF: 0.00 AC: 0 AN: 1610

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 3834

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 189

European-Non Finnish (NFE) AF: 0.00193 AC: 88 AN: 45637

Other (OTH) AF: 0.00165 AC: 2 AN: 1210

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.29
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;