X-71141301-A-ACAGCAACACCAG

Variant names:

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_StrongBS1BS2

The NM_005120.3(MED12):c.6348_6359dupCCAGCAGCAACA(p.His2116_Gln2119dup) variant causes a disruptive 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 (★★).

Frequency

Genomes: 𝑓 0.022 ( 26 hom., 649 hem., cov: 22)

Exomes 𝑓: 0.026 ( 356 hom. 8829 hem. )

Consequence

MED12
NM_005120.3 disruptive_inframe_insertion

Scores

Not classified

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11

Conservation

PhyloP100: 4.18

Variant links:

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]

MED12 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -16 ACMG points.

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 GnomAd4 at 26 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MED12	NM_005120.3 link	c.6348_6359dupCCAGCAGCAACA	p.His2116_Gln2119dup	disruptive_inframe_insertion	Exon 43 of 45	ENST00000374080.8	NP_005111.2	Q93074-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MED12	ENST00000374080.8 link	c.6348_6359dupCCAGCAGCAACA	p.His2116_Gln2119dup	disruptive_inframe_insertion	Exon 43 of 45	1	NM_005120.3	ENSP00000363193.3		Q93074-1

Frequencies

GnomAD3 genomes

AF:

0.0222

AC:

2458

AN:

110863

Hom.:

Cov.:

AF XY:

0.0195

AC XY:

647

AN XY:

33233

show subpopulations

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.:

AF XY:

0.0221

AC XY:

897

AN XY:

40594

show subpopulations

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.:

AF XY:

0.0257

AC XY:

8829

AN XY:

343977

show subpopulations

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.:

Cov.:

AF XY:

0.0195

AC XY:

649

AN XY:

33297

show subpopulations

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:

AN:

2522

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:7

Jul 09, 2014

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was found in TAADV2-PANCARD,TAAD,TAADV2-1,MACRO-BRAIN -

Oct 31, 2015

Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 29, 2015

Genetic Services Laboratory, University of Chicago

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided

Benign:2

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

FG syndrome

Benign:1

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Cardiovascular phenotype

Benign:1

Aug 01, 2017

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Name

Calibrated prediction

Score

Prediction

Splicing

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over