chrX-71132767-CCTCTTCTCTTCTCTTCTCTTCTCTTCTCTTCTCTT-C

Position:

• chrX-71132767-CCTCTTCTCTTCTCTTCTCTTCTCTTCTCTTCTCTT-C

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP6 BS1 BS2

The ENST00000374080.8(MED12):​c.4416-50_4416-16del variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00488 in 653,256 control chromosomes in the GnomAD database, including 12 homozygotes. There are 1,013 hemizygotes in GnomAD. Variant has been reported in Lovd as Likely benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.0052 (2 hom., 116 hem., cov: 0)
  • Exomes 𝑓: 0.0048 (10 hom. 897 hem.)
• Consequence: MED12 ENST00000374080.8 intron
• Clinical Significance: Not reported in ClinVar
• 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-CCTCTTCTCTTCTCTTCTCTTCTCTTCTCTTCTCTT-C is Benign according to our data. Variant chrX-71132767-CCTCTTCTCTTCTCTTCTCTTCTCTTCTCTTCTCTT-C is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00516 (468/90666) while in subpopulation NFE AF= 0.00774 (353/45636). AF 95% confidence interval is 0.00707. There are 2 homozygotes in gnomad4. There are 116 alleles in male gnomad4 subpopulation. Median coverage is 0. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 2 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MED12	NM_005120.3	c.4416-50_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.4416-50_4416-16del		intron_variant		1	NM_005120.3	ENSP00000363193	P4

Frequencies

GnomAD3 genomes AF: 0.00516 AC: 468 AN: 90626 Hom.: 2 Cov.: 0 AF XY: 0.00620 AC XY: 116 AN XY: 18708

Gnomad AFR AF: 0.00151

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00385

Gnomad ASJ AF: 0.00130

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00247

Gnomad FIN AF: 0.00835

Gnomad MID AF: 0.00476

Gnomad NFE AF: 0.00773

Gnomad OTH AF: 0.00588

GnomAD4 exome AF: 0.00483 AC: 2717 AN: 562590 Hom.: 10 AF XY: 0.00550 AC XY: 897 AN XY: 162968

Gnomad4 AFR exome AF: 0.000945

Gnomad4 AMR exome AF: 0.00185

Gnomad4 ASJ exome AF: 0.00113

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000984

Gnomad4 FIN exome AF: 0.00487

Gnomad4 NFE exome AF: 0.00590

Gnomad4 OTH exome AF: 0.00486

GnomAD4 genome AF: 0.00516 AC: 468 AN: 90666 Hom.: 2 Cov.: 0 AF XY: 0.00619 AC XY: 116 AN XY: 18748

Gnomad4 AFR AF: 0.00150

Gnomad4 AMR AF: 0.00384

Gnomad4 ASJ AF: 0.00130

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00248

Gnomad4 FIN AF: 0.00835

Gnomad4 NFE AF: 0.00774

Gnomad4 OTH AF: 0.00579

ClinVar

Not reported in ClinVar

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;