X-71132767-CCTCTTCTCTTCTCTTCTCTTCTCTTCTCTTCTCTTCTCTTCTCTT-CCTCTTCTCTTCTCTTCTCTTCTCTTCTCTTCTCTTCTCTTCTCTTCTCTTCTCTTCTCTTCTCTTCTCTTCTCTTCTCTT

Variant names:

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

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS1

The NM_005120.3(MED12):​c.4416-50_4416-16dupCTTCTCTTCTCTTCTCTTCTCTTCTCTTCTCTTCT 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 0.00019 (0 hom., 0 hem., cov: 0)
  • Exomes 𝑓: 0.00016 (1 hom. 36 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: Likely_benign. The variant received -4 ACMG points.

• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.000188 (17/90627) while in subpopulation EAS AF = 0.000388 (1/2580). AF 95% confidence interval is 0.000168. There are 0 homozygotes in GnomAd4. There are 0 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MED12	NM_005120.3	c.4416-50_4416-16dupCTTCTCTTCTCTTCTCTTCTCTTCTCTTCTCTTCT		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_4416-77insCTCTTCTCTTCTCTTCTCTTCTCTTCTCTTCTCTT		intron_variant	Intron 31 of 44	1	NM_005120.3	ENSP00000363193.3

Frequencies

GnomAD3 genomes AF: 0.000188 AC: 17 AN: 90627 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000248

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000388

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000261

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000285

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.000156 AC: 88 AN: 562789 Hom.: 1 AF XY: 0.000221 AC XY: 36 AN XY: 163151

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

African (AFR) AF: 0.00 AC: 0 AN: 14814

American (AMR) AF: 0.000324 AC: 7 AN: 21585

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

East Asian (EAS) AF: 0.0000429 AC: 1 AN: 23314

South Asian (SAS) AF: 0.0000868 AC: 3 AN: 34554

European-Finnish (FIN) AF: 0.000239 AC: 8 AN: 33468

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

European-Non Finnish (NFE) AF: 0.000169 AC: 66 AN: 391567

Other (OTH) AF: 0.000110 AC: 3 AN: 27362

⚠️ 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: 0.000188 AC: 17 AN: 90627 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 18709

African (AFR) AF: 0.00 AC: 0 AN: 24570

American (AMR) AF: 0.000248 AC: 2 AN: 8062

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

East Asian (EAS) AF: 0.000388 AC: 1 AN: 2580

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

European-Finnish (FIN) AF: 0.000261 AC: 1 AN: 3834

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

European-Non Finnish (NFE) AF: 0.000285 AC: 13 AN: 45645

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

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.29

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;