rs773940605

Variant names:

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP3BP6_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. It is difficult to determine the true allele frequency of this variant because it is of type INS_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. Q2120Q) has been classified 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

Publications

5 publications found

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 Gene-Disease associations (from GenCC):

FG syndrome 1
Inheritance: XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), G2P, Orphanet
MED12-related intellectual disability syndrome
Inheritance: XL Classification: DEFINITIVE Submitted by: ClinGen
X-linked intellectual disability with marfanoid habitus
Inheritance: XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), G2P, Orphanet
blepharophimosis - intellectual disability syndrome, MKB type
Inheritance: XL Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet
cholestasis-pigmentary retinopathy-cleft palate syndrome
Inheritance: XL Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)

MED12 links:

ENSG00000228427 (HGNC:):

ENSG00000228427 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 Benign/Likely_benign. ClinVar VariationId 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 the male GnomAd4 subpopulation. Median coverage is 22. This position passed quality control check.

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.:

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

GnomAD2 exomes

AF:

0.0232

AC:

2640

AN:

113704

AF XY:

0.0221

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 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

African (AFR)

AF:

0.0145

AC:

361

AN:

24892

American (AMR)

AF:

0.0138

AC:

386

AN:

27907

Ashkenazi Jewish (ASJ)

AF:

0.0869

AC:

1618

AN:

18622

East Asian (EAS)

AF:

0.000111

AC:

AN:

27132

South Asian (SAS)

AF:

0.0107

AC:

532

AN:

49853

European-Finnish (FIN)

AF:

0.0393

AC:

1480

AN:

37629

Middle Eastern (MID)

AF:

0.0559

AC:

228

AN:

4080

European-Non Finnish (NFE)

AF:

0.0263

AC:

21485

AN:

818388

Other (OTH)

AF:

0.0319

AC:

1416

AN:

44354

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.472

Heterozygous variant carriers

920

1841

2761

3682

4602

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

828

1656

2484

3312

4140

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0222

AC:

2459

AN:

110917

Hom.:

Cov.:

AF XY:

0.0195

AC XY:

649

AN XY:

33297

show subpopulations

African (AFR)

AF:

0.0149

AC:

455

AN:

30494

American (AMR)

AF:

0.0125

AC:

131

AN:

10470

Ashkenazi Jewish (ASJ)

AF:

0.0836

AC:

219

AN:

2620

East Asian (EAS)

AF:

0.000566

AC:

AN:

3531

South Asian (SAS)

AF:

0.00859

AC:

AN:

2677

European-Finnish (FIN)

AF:

0.0372

AC:

222

AN:

5960

Middle Eastern (MID)

AF:

0.0751

AC:

AN:

213

European-Non Finnish (NFE)

AF:

0.0256

AC:

1352

AN:

52776

Other (OTH)

AF:

0.0246

AC:

AN:

1507

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

178

266

355

444

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

104

130

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

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

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 -

Jul 09, 2014

Eurofins Ntd Llc (ga)

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

- -

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

Significance:Benign

Review Status:no assertion criteria provided

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

- -

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

- -

not provided

Benign:2

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

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

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

PhyloP100

4.2

Mutation Taster

=89/11

polymorphism (auto)

(source)

Splicing

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over