chrX-71132767-C-CCTCTTCTCTTCTCTTCTCTT

Variant names:

• chrX-71132767-C-CCTCTTCTCTTCTCTTCTCTT
• rs56658066
• NM_005120.3:c.4416-35_4416-16dupCTTCTCTTCTCTTCTCTTCT

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BS1_Supporting BS2

The NM_005120.3(MED12):​c.4416-35_4416-16dupCTTCTCTTCTCTTCTCTTCT 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. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.011 (19 hom., 118 hem., cov: 0)
  • Exomes 𝑓: 0.0099 (118 hom. 1792 hem.)
  • Failed GnomAD Quality Control
• Consequence: MED12 NM_005120.3 intron
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• 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: 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: Likely_benign. The variant received -5 ACMG points.

• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.0105 (954/90655) while in subpopulation EAS AF = 0.0128 (33/2570). AF 95% confidence interval is 0.0118. There are 19 homozygotes in GnomAd4. There are 118 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAd4 at 19 XL gene

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.4416-35_4416-16dupCTTCTCTTCTCTTCTCTTCT		intron	N/A	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.4416-78_4416-77insCTCTTCTCTTCTCTTCTCTT		intron	N/A	ENSP00000363193.3	Q93074-1
	MED12	ENST00000374102.6	TSL:1	c.4416-78_4416-77insCTCTTCTCTTCTCTTCTCTT		intron	N/A	ENSP00000363215.2	Q93074-2
	MED12	ENST00000938012.1		c.4458-78_4458-77insCTCTTCTCTTCTCTTCTCTT		intron	N/A	ENSP00000608071.1

Frequencies

GnomAD3 genomes AF: 0.0105 AC: 952 AN: 90615 Hom.: 18 Cov.: 0

Gnomad AFR AF: 0.00232

Gnomad AMI AF: 0.00166

Gnomad AMR AF: 0.00980

Gnomad ASJ AF: 0.0238

Gnomad EAS AF: 0.0132

Gnomad SAS AF: 0.00802

Gnomad FIN AF: 0.0324

Gnomad MID AF: 0.00952

Gnomad NFE AF: 0.0127

Gnomad OTH AF: 0.00756

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00987 AC: 5552 AN: 562300 Hom.: 118 AF XY: 0.0110 AC XY: 1792 AN XY: 162916

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

African (AFR) AF: 0.00169 AC: 25 AN: 14811

American (AMR) AF: 0.0104 AC: 225 AN: 21573

Ashkenazi Jewish (ASJ) AF: 0.0196 AC: 278 AN: 14163

East Asian (EAS) AF: 0.0117 AC: 273 AN: 23289

South Asian (SAS) AF: 0.00771 AC: 266 AN: 34521

European-Finnish (FIN) AF: 0.0407 AC: 1359 AN: 33363

Middle Eastern (MID) AF: 0.00677 AC: 13 AN: 1921

European-Non Finnish (NFE) AF: 0.00716 AC: 2802 AN: 391322

Other (OTH) AF: 0.0114 AC: 311 AN: 27337

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0105 AC: 954 AN: 90655 Hom.: 19 Cov.: 0 AF XY: 0.00629 AC XY: 118 AN XY: 18749

African (AFR) AF: 0.00231 AC: 57 AN: 24623

American (AMR) AF: 0.0103 AC: 83 AN: 8074

Ashkenazi Jewish (ASJ) AF: 0.0238 AC: 55 AN: 2315

East Asian (EAS) AF: 0.0128 AC: 33 AN: 2570

South Asian (SAS) AF: 0.00807 AC: 13 AN: 1610

European-Finnish (FIN) AF: 0.0324 AC: 124 AN: 3826

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

European-Non Finnish (NFE) AF: 0.0127 AC: 578 AN: 45637

Other (OTH) AF: 0.00744 AC: 9 AN: 1210

Alfa AF: 0.00 Hom.: 352

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

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;