X-71132767-CCTCTTCTCTTCTCTTCTCTTCTCTTCTCTTCTCTTCTCTTCTCTT-CCTCTTCTCTTCTCTTCTCTTCTCTTCTCTTCTCTTCTCTTCTCTTCTCTT

Position:

• chrX-71132767-CCTCTTCTCTTCTCTTCTCTTCTCTTCTCTTCTCTTCTCTTCTCTT-CCTCTTCTCTTCTCTTCTCTTCTCTTCTCTTCTCTTCTCTTCTCTTCTCTT

Variant summary

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

The ENST00000374080.8(MED12):​c.4416-20_4416-16dup variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.101 in 645,426 control chromosomes in the GnomAD database, including 3,995 homozygotes. There are 14,901 hemizygotes in GnomAD. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.13 (911 hom., 1504 hem., cov: 0)
  • Exomes 𝑓: 0.096 (3084 hom. 13397 hem.)
• Consequence: MED12 ENST00000374080.8 intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: -0.294

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-C-CCTCTT is Benign according to our data. Variant chrX-71132767-C-CCTCTT is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 95250.We mark this variant Likely_benign, oryginal submissions are: {Benign=1, Uncertain_significance=1}.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.227 is higher than 0.05.

Transcripts

RefSeq

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

Frequencies

GnomAD3 genomes AF: 0.134 AC: 12102 AN: 90401 Hom.: 910 Cov.: 0 AF XY: 0.0806 AC XY: 1504 AN XY: 18663

Gnomad AFR AF: 0.0807

Gnomad AMI AF: 0.211

Gnomad AMR AF: 0.124

Gnomad ASJ AF: 0.110

Gnomad EAS AF: 0.243

Gnomad SAS AF: 0.164

Gnomad FIN AF: 0.133

Gnomad MID AF: 0.120

Gnomad NFE AF: 0.157

Gnomad OTH AF: 0.130

GnomAD4 exome AF: 0.0956 AC: 53064 AN: 554984 Hom.: 3084 AF XY: 0.0853 AC XY: 13397 AN XY: 157100

Gnomad4 AFR exome AF: 0.0541

Gnomad4 AMR exome AF: 0.102

Gnomad4 ASJ exome AF: 0.0779

Gnomad4 EAS exome AF: 0.217

Gnomad4 SAS exome AF: 0.135

Gnomad4 FIN exome AF: 0.154

Gnomad4 NFE exome AF: 0.0813

Gnomad4 OTH exome AF: 0.106

GnomAD4 genome AF: 0.134 AC: 12094 AN: 90442 Hom.: 911 Cov.: 0 AF XY: 0.0804 AC XY: 1504 AN XY: 18704

Gnomad4 AFR AF: 0.0805

Gnomad4 AMR AF: 0.124

Gnomad4 ASJ AF: 0.110

Gnomad4 EAS AF: 0.243

Gnomad4 SAS AF: 0.164

Gnomad4 FIN AF: 0.133

Gnomad4 NFE AF: 0.157

Gnomad4 OTH AF: 0.128

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 14, 2014	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 19, 2019	- -

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;