X-71132767-CCTCTTCTCTTCTCTTCTCTTCTCTTCTCTTCTCTTCTCTTCTCTT-CCTCTTCTCTTCTCTTCTCTTCTCTTCTCTTCTCTTCTCTTCTCTTCTCTTCTCTTCTCTT

Position:

• chrX-71132767-CCTCTTCTCTTCTCTTCTCTTCTCTTCTCTTCTCTTCTCTTCTCTT-CCTCTTCTCTTCTCTTCTCTTCTCTTCTCTTCTCTTCTCTTCTCTTCTCTTCTCTTCTCTT

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP6_Moderate BS1 BS2

The ENST00000374080.8(MED12):​c.4416-30_4416-16dup variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0204 in 561,748 control chromosomes in the GnomAD database, including 308 homozygotes. There are 3,721 hemizygotes in GnomAD. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.021 (36 hom., 243 hem., cov: 0)
  • Exomes 𝑓: 0.020 (308 hom. 3721 hem.)
  • Failed GnomAD Quality Control
• Consequence: MED12 ENST00000374080.8 intron
• Clinical Significance: Benign criteria provided, single submitter 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 -10 ACMG points.

• BP6: Variant X-71132767-C-CCTCTTCTCTTCTCTT is Benign according to our data. Variant chrX-71132767-C-CCTCTTCTCTTCTCTT is described in ClinVar as [Benign]. Clinvar id is 1221738.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population eas. gnomad4_exome allele frequency = 0.0204 (11461/561748) while in subpopulation EAS AF= 0.0434 (1010/23247). AF 95% confidence interval is 0.0412. There are 308 homozygotes in gnomad4_exome. There are 3721 alleles in male gnomad4_exome subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 308 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MED12	NM_005120.3	c.4416-30_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.4416-30_4416-16dup		intron_variant		1	NM_005120.3	ENSP00000363193	P4

Frequencies

GnomAD3 genomes AF: 0.00 AC: 1930 AN: 90611 Hom.: 36 Cov.: 0 AF XY: 0.0130 AC XY: 244 AN XY: 18707 FAILED QC

Gnomad AFR AF: 0.00562

Gnomad AMI AF: 0.00832

Gnomad AMR AF: 0.0189

Gnomad ASJ AF: 0.0168

Gnomad EAS AF: 0.0415

Gnomad SAS AF: 0.0210

Gnomad FIN AF: 0.0431

Gnomad MID AF: 0.0143

Gnomad NFE AF: 0.0276

Gnomad OTH AF: 0.0227

GnomAD4 exome AF: 0.0204 AC: 11461 AN: 561748 Hom.: 308 AF XY: 0.0229 AC XY: 3721 AN XY: 162530

Gnomad4 AFR exome AF: 0.00493

Gnomad4 AMR exome AF: 0.0132

Gnomad4 ASJ exome AF: 0.0165

Gnomad4 EAS exome AF: 0.0434

Gnomad4 SAS exome AF: 0.0267

Gnomad4 FIN exome AF: 0.0559

Gnomad4 NFE exome AF: 0.0164

Gnomad4 OTH exome AF: 0.0229

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.0213 AC: 1928 AN: 90651 Hom.: 36 Cov.: 0 AF XY: 0.0130 AC XY: 243 AN XY: 18747

Gnomad4 AFR AF: 0.00560

Gnomad4 AMR AF: 0.0188

Gnomad4 ASJ AF: 0.0168

Gnomad4 EAS AF: 0.0416

Gnomad4 SAS AF: 0.0205

Gnomad4 FIN AF: 0.0431

Gnomad4 NFE AF: 0.0276

Gnomad4 OTH AF: 0.0223

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Nov 14, 2019

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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;