rs41298482

chrX-71136854-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_005120.3(MED12):c.5401-25C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.126 in 1,208,219 control chromosomes in the GnomAD database, including 6,999 homozygotes. There are 50,986 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.15 (1079 hom., 4684 hem., cov: 22)
  • Exomes 𝑓: 0.12 (5920 hom. 46302 hem.)
• Consequence: MED12 NM_005120.3 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.98

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant X-71136854-C-T is Benign according to our data. Variant chrX-71136854-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 259639.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.232 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MED12	NM_005120.3	c.5401-25C>T		intron_variant		ENST00000374080.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MED12	ENST00000374080.8	c.5401-25C>T		intron_variant		1	NM_005120.3	P4

Frequencies

GnomAD3 genomes AF: 0.151 AC: 16718 AN: 110808 Hom.: 1076 Cov.: 22 AF XY: 0.141 AC XY: 4669 AN XY: 33042

Gnomad AFR AF: 0.237

Gnomad AMI AF: 0.0247

Gnomad AMR AF: 0.111

Gnomad ASJ AF: 0.0909

Gnomad EAS AF: 0.128

Gnomad SAS AF: 0.212

Gnomad FIN AF: 0.107

Gnomad MID AF: 0.134

Gnomad NFE AF: 0.118

Gnomad OTH AF: 0.138

GnomAD3 exomes AF: 0.135 AC: 24178 AN: 179137 Hom.: 1236 AF XY: 0.137 AC XY: 8967 AN XY: 65613

Gnomad AFR exome AF: 0.240

Gnomad AMR exome AF: 0.102

Gnomad ASJ exome AF: 0.0909

Gnomad EAS exome AF: 0.152

Gnomad SAS exome AF: 0.234

Gnomad FIN exome AF: 0.115

Gnomad NFE exome AF: 0.113

Gnomad OTH exome AF: 0.117

GnomAD4 exome AF: 0.124 AC: 135992 AN: 1097357 Hom.: 5920 Cov.: 33 AF XY: 0.128 AC XY: 46302 AN XY: 362885

Gnomad4 AFR exome AF: 0.239

Gnomad4 AMR exome AF: 0.102

Gnomad4 ASJ exome AF: 0.0913

Gnomad4 EAS exome AF: 0.118

Gnomad4 SAS exome AF: 0.223

Gnomad4 FIN exome AF: 0.116

Gnomad4 NFE exome AF: 0.116

Gnomad4 OTH exome AF: 0.134

GnomAD4 genome AF: 0.151 AC: 16733 AN: 110862 Hom.: 1079 Cov.: 22 AF XY: 0.141 AC XY: 4684 AN XY: 33106

Gnomad4 AFR AF: 0.237

Gnomad4 AMR AF: 0.110

Gnomad4 ASJ AF: 0.0909

Gnomad4 EAS AF: 0.128

Gnomad4 SAS AF: 0.213

Gnomad4 FIN AF: 0.107

Gnomad4 NFE AF: 0.118

Gnomad4 OTH AF: 0.148

Alfa AF: 0.131 Hom.: 1048

Bravo AF: 0.154

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

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- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 26, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
Cadd	Benign	15
Dann	Benign	0.64

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.19		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs41298482; hg19: chrX-70356704; COSMIC: COSV61332980;