X-71132767-CCTCTTCTCTTCTCTTCTCTTCTCTTCTCTTCTCTTCTCTTCTCTT-CCTCTTCTCTTCTCTTCTCTTCTCTTCTCTTCTCTTCTCTTCTCTTCTCTTCTCTTCTCTTCTCTT

Variant names:

• chrX-71132767-C-CCTCTTCTCTTCTCTTCTCTT
• rs56658066
• NM_005120.3:c.4416-35_4416-16dupCTTCTCTTCTCTTCTCTTCT

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BS1_Supporting BS2

The NM_005120.3(MED12):​c.4416-35_4416-16dupCTTCTCTTCTCTTCTCTTCT variant causes a intron change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.011 (19 hom., 118 hem., cov: 0)
  • Exomes 𝑓: 0.0099 (118 hom. 1792 hem.)
  • Failed GnomAD Quality Control
• Consequence: MED12 NM_005120.3 intron
• Clinical Significance: Uncertain significance criteria provided, single submitter U: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 Likely_benign. Variant got -5 ACMG points.

• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.0105 (954/90655) while in subpopulation EAS AF= 0.0128 (33/2570). AF 95% confidence interval is 0.0118. There are 19 homozygotes in gnomad4. There are 118 alleles in male gnomad4 subpopulation. Median coverage is 0. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAd4 at 19 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MED12	NM_005120.3	c.4416-35_4416-16dupCTTCTCTTCTCTTCTCTTCT		intron_variant	Intron 31 of 44	ENST00000374080.8	NP_005111.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MED12	ENST00000374080.8	c.4416-78_4416-77insCTCTTCTCTTCTCTTCTCTT		intron_variant	Intron 31 of 44	1	NM_005120.3	ENSP00000363193.3

Frequencies

GnomAD3 genomes AF: 0.0105 AC: 952 AN: 90615 Hom.: 18 Cov.: 0 AF XY: 0.00631 AC XY: 118 AN XY: 18709

Gnomad AFR AF: 0.00232

Gnomad AMI AF: 0.00166

Gnomad AMR AF: 0.00980

Gnomad ASJ AF: 0.0238

Gnomad EAS AF: 0.0132

Gnomad SAS AF: 0.00802

Gnomad FIN AF: 0.0324

Gnomad MID AF: 0.00952

Gnomad NFE AF: 0.0127

Gnomad OTH AF: 0.00756

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00987 AC: 5552 AN: 562300 Hom.: 118 AF XY: 0.0110 AC XY: 1792 AN XY: 162916

Gnomad4 AFR exome AF: 0.00169

Gnomad4 AMR exome AF: 0.0104

Gnomad4 ASJ exome AF: 0.0196

Gnomad4 EAS exome AF: 0.0117

Gnomad4 SAS exome AF: 0.00771

Gnomad4 FIN exome AF: 0.0407

Gnomad4 NFE exome AF: 0.00716

Gnomad4 OTH exome AF: 0.0114

GnomAD4 genome AF: 0.0105 AC: 954 AN: 90655 Hom.: 19 Cov.: 0 AF XY: 0.00629 AC XY: 118 AN XY: 18749

Gnomad4 AFR AF: 0.00231

Gnomad4 AMR AF: 0.0103

Gnomad4 ASJ AF: 0.0238

Gnomad4 EAS AF: 0.0128

Gnomad4 SAS AF: 0.00807

Gnomad4 FIN AF: 0.0324

Gnomad4 NFE AF: 0.0127

Gnomad4 OTH AF: 0.00744

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Aug 20, 2014

Eurofins Ntd Llc (ga)

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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;