X-71132767-CCTCTTCTCTTCTCTTCTCTTCTCTTCTCTTCTCTTCTCTTCTCTT-CCTCTTCTCTTCTCTTCTCTTCTCTTCTCTTCTCTTCTCTT

Position:

• chrX-71132767-CCTCTTCTCTTCTCTTCTCTTCTCTTCTCTTCTCTTCTCTTCTCTT-CCTCTTCTCTTCTCTTCTCTTCTCTTCTCTTCTCTTCTCTT

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_005120.3(MED12):​c.4416-20_4416-16del variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0798 in 651,266 control chromosomes in the GnomAD database, including 2,461 homozygotes. There are 14,295 hemizygotes in GnomAD. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.13 (780 hom., 1731 hem., cov: 0)
  • Exomes 𝑓: 0.072 (1681 hom. 12564 hem.)
• Consequence: MED12 NM_005120.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.0730

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 -16 ACMG points.

• BP6: Variant X-71132767-CCTCTT-C is Benign according to our data. Variant chrX-71132767-CCTCTT-C is described in ClinVar as [Benign]. Clinvar id is 95249.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-71132767-CCTCTT-C is described in Lovd as [Likely_benign]. Variant chrX-71132767-CCTCTT-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.196 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MED12	NM_005120.3	c.4416-20_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.4416-20_4416-16del		intron_variant		1	NM_005120.3	ENSP00000363193	P4

Frequencies

GnomAD3 genomes AF: 0.130 AC: 11760 AN: 90423 Hom.: 784 Cov.: 0 AF XY: 0.0925 AC XY: 1726 AN XY: 18667

Gnomad AFR AF: 0.201

Gnomad AMI AF: 0.0266

Gnomad AMR AF: 0.149

Gnomad ASJ AF: 0.0722

Gnomad EAS AF: 0.0970

Gnomad SAS AF: 0.0834

Gnomad FIN AF: 0.116

Gnomad MID AF: 0.0524

Gnomad NFE AF: 0.0981

Gnomad OTH AF: 0.128

GnomAD4 exome AF: 0.0717 AC: 40210 AN: 560804 Hom.: 1681 AF XY: 0.0777 AC XY: 12564 AN XY: 161782

Gnomad4 AFR exome AF: 0.153

Gnomad4 AMR exome AF: 0.158

Gnomad4 ASJ exome AF: 0.0663

Gnomad4 EAS exome AF: 0.124

Gnomad4 SAS exome AF: 0.0739

Gnomad4 FIN exome AF: 0.132

Gnomad4 NFE exome AF: 0.0548

Gnomad4 OTH exome AF: 0.0836

GnomAD4 genome AF: 0.130 AC: 11757 AN: 90462 Hom.: 780 Cov.: 0 AF XY: 0.0925 AC XY: 1731 AN XY: 18706

Gnomad4 AFR AF: 0.201

Gnomad4 AMR AF: 0.149

Gnomad4 ASJ AF: 0.0722

Gnomad4 EAS AF: 0.0975

Gnomad4 SAS AF: 0.0815

Gnomad4 FIN AF: 0.116

Gnomad4 NFE AF: 0.0981

Gnomad4 OTH AF: 0.125

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 29, 2012	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 01, 2015	This variant was found in TAADV2-PANCARD -

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;