X-71132767-CCTCTTCTCTTCTCTTCTCTTCTCTTCTCTTCTCTTCTCTTCTCTT-CCTCTTCTCTTCTCTTCTCTTCTCTTCTCTTCTCTT

Position:

• chrX-71132767-CCTCTTCTCTTCTCTTCTCTTCTCTTCTCTTCTCTTCTCTTCTCTT-CCTCTTCTCTTCTCTTCTCTTCTCTTCTCTTCTCTT

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP6 BA1

The NM_005120.3(MED12):​c.4416-25_4416-16del variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0168 in 652,215 control chromosomes in the GnomAD database, including 230 homozygotes. There are 2,887 hemizygotes in GnomAD. Variant has been reported in ClinVar as Likely benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.042 (118 hom., 582 hem., cov: 0)
  • Exomes 𝑓: 0.013 (112 hom. 2305 hem.)
• Consequence: MED12 NM_005120.3 intron
• Clinical Significance: Likely benign no assertion criteria provided B:1
• Conservation: PhyloP100: 0.312

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]

ACMG classification

Verdict is Benign. Variant got -9 ACMG points.

• BP6: Variant X-71132767-CCTCTTCTCTT-C is Benign according to our data. Variant chrX-71132767-CCTCTTCTCTT-C is described in ClinVar as [Likely_benign]. Clinvar id is 3055527.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chrX-71132767-CCTCTTCTCTT-C is described in Lovd as [Likely_benign]. Variant chrX-71132767-CCTCTTCTCTT-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.098 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MED12	NM_005120.3	c.4416-25_4416-16del		intron_variant		ENST00000374080.8	NP_005111.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MED12	ENST00000374080.8	c.4416-25_4416-16del		intron_variant		1	NM_005120.3	ENSP00000363193	P4

Frequencies

GnomAD3 genomes AF: 0.0419 AC: 3796 AN: 90594 Hom.: 117 Cov.: 0 AF XY: 0.0311 AC XY: 581 AN XY: 18700

Gnomad AFR AF: 0.101

Gnomad AMI AF: 0.00666

Gnomad AMR AF: 0.0444

Gnomad ASJ AF: 0.0337

Gnomad EAS AF: 0.0190

Gnomad SAS AF: 0.0148

Gnomad FIN AF: 0.00261

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.0161

Gnomad OTH AF: 0.0403

GnomAD4 exome AF: 0.0127 AC: 7152 AN: 561581 Hom.: 112 AF XY: 0.0142 AC XY: 2305 AN XY: 162117

Gnomad4 AFR exome AF: 0.0727

Gnomad4 AMR exome AF: 0.0269

Gnomad4 ASJ exome AF: 0.0292

Gnomad4 EAS exome AF: 0.0192

Gnomad4 SAS exome AF: 0.0180

Gnomad4 FIN exome AF: 0.00327

Gnomad4 NFE exome AF: 0.00848

Gnomad4 OTH exome AF: 0.0206

GnomAD4 genome AF: 0.0419 AC: 3799 AN: 90634 Hom.: 118 Cov.: 0 AF XY: 0.0311 AC XY: 582 AN XY: 18740

Gnomad4 AFR AF: 0.101

Gnomad4 AMR AF: 0.0444

Gnomad4 ASJ AF: 0.0337

Gnomad4 EAS AF: 0.0191

Gnomad4 SAS AF: 0.0149

Gnomad4 FIN AF: 0.00261

Gnomad4 NFE AF: 0.0161

Gnomad4 OTH AF: 0.0388

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

Submissions by phenotype

MED12-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 30, 2020

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs56658066; hg19: chrX-70352617;