rs398124200

chrX-71141301-A-ACAGCAACACCAG

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP3 BP6_Very_Strong BS1 BS2

The NM_005120.3(MED12):c.6348_6359dup(p.His2116_Gln2119dup) variant causes a inframe insertion change. The variant allele was found at a frequency of 0.0258 in 1,163,774 control chromosomes in the GnomAD database, including 382 homozygotes. There are 9,478 hemizygotes in GnomAD. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. Q2113Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.022 (26 hom., 649 hem., cov: 22)
  • Exomes 𝑓: 0.026 (356 hom. 8829 hem.)
• Consequence: MED12 NM_005120.3 inframe_insertion
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 4.18

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 -17 ACMG points.

• BP3: Nonframeshift variant in repetitive region in NM_005120.3
• BP6: Variant X-71141301-A-ACAGCAACACCAG is Benign according to our data. Variant chrX-71141301-A-ACAGCAACACCAG is described in ClinVar as [Likely_benign]. Clinvar id is 95256.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0222 (2459/110917) while in subpopulation NFE AF= 0.0256 (1352/52776). AF 95% confidence interval is 0.0245. There are 26 homozygotes in gnomad4. There are 649 alleles in male gnomad4 subpopulation. Median coverage is 22. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 26 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MED12	NM_005120.3	c.6348_6359dup	p.His2116_Gln2119dup	inframe_insertion	43/45	ENST00000374080.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MED12	ENST00000374080.8	c.6348_6359dup	p.His2116_Gln2119dup	inframe_insertion	43/45	1	NM_005120.3	P4

Frequencies

GnomAD3 genomes AF: 0.0222 AC: 2458 AN: 110863 Hom.: 26 Cov.: 22 AF XY: 0.0195 AC XY: 647 AN XY: 33233

Gnomad AFR AF: 0.0149

Gnomad AMI AF: 0.00299

Gnomad AMR AF: 0.0125

Gnomad ASJ AF: 0.0836

Gnomad EAS AF: 0.000565

Gnomad SAS AF: 0.00819

Gnomad FIN AF: 0.0372

Gnomad MID AF: 0.0726

Gnomad NFE AF: 0.0256

Gnomad OTH AF: 0.0249

GnomAD3 exomes AF: 0.0232 AC: 2640 AN: 113704 Hom.: 47 AF XY: 0.0221 AC XY: 897 AN XY: 40594

Gnomad AFR exome AF: 0.0131

Gnomad AMR exome AF: 0.0132

Gnomad ASJ exome AF: 0.0828

Gnomad EAS exome AF: 0.000243

Gnomad SAS exome AF: 0.0119

Gnomad FIN exome AF: 0.0350

Gnomad NFE exome AF: 0.0247

Gnomad OTH exome AF: 0.0326

GnomAD4 exome AF: 0.0261 AC: 27509 AN: 1052857 Hom.: 356 Cov.: 33 AF XY: 0.0257 AC XY: 8829 AN XY: 343977

Gnomad4 AFR exome AF: 0.0145

Gnomad4 AMR exome AF: 0.0138

Gnomad4 ASJ exome AF: 0.0869

Gnomad4 EAS exome AF: 0.000111

Gnomad4 SAS exome AF: 0.0107

Gnomad4 FIN exome AF: 0.0393

Gnomad4 NFE exome AF: 0.0263

Gnomad4 OTH exome AF: 0.0319

GnomAD4 genome AF: 0.0222 AC: 2459 AN: 110917 Hom.: 26 Cov.: 22 AF XY: 0.0195 AC XY: 649 AN XY: 33297

Gnomad4 AFR AF: 0.0149

Gnomad4 AMR AF: 0.0125

Gnomad4 ASJ AF: 0.0836

Gnomad4 EAS AF: 0.000566

Gnomad4 SAS AF: 0.00859

Gnomad4 FIN AF: 0.0372

Gnomad4 NFE AF: 0.0256

Gnomad4 OTH AF: 0.0246

Alfa AF: 0.0331 Hom.: 229

Asia WGS AF: 0.00597 AC: 15 AN: 2522

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:7

Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Sep 29, 2015	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 09, 2014	- -
Benign, criteria provided, single submitter	clinical testing	Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	Oct 31, 2015	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	This variant was found in TAADV2-PANCARD,TAAD,TAADV2-1,MACRO-BRAIN -
Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

not provided Benign:2

Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

FG syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Cardiovascular phenotype Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 01, 2017

General population or subpopulation frequency is too high to be a pathogenic mutation based on disease/syndrome prevalence and penetrance;Other strong data supporting benign classification -

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: rs398124200; hg19: chrX-70361151;