chrX-71119648-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_005120.3(MED12):c.205-38C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.281 in 1,195,049 control chromosomes in the GnomAD database, including 36,042 homozygotes. There are 107,131 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 0.22 ( 2609 hom., 7062 hem., cov: 23)

Exomes 𝑓: 0.29 ( 33433 hom. 100069 hem. )

Consequence

MED12
NM_005120.3 intron

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 0.375

Publications

4 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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.58).

BP6

Variant X-71119648-C-T is Benign according to our data. Variant chrX-71119648-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 259633.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.315 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MED12	NM_005120.3 link	c.205-38C>T		intron_variant	Intron 2 of 44	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.205-38C>T		intron_variant	Intron 2 of 44	1	NM_005120.3	ENSP00000363193.3		Q93074-1

Frequencies

GnomAD3 genomes

AF:

0.219

AC:

24462

AN:

111785

Hom.:

2611

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0558

Gnomad AMI

AF:

0.465

Gnomad AMR

AF:

0.197

Gnomad ASJ

AF:

0.405

Gnomad EAS

AF:

0.00279

Gnomad SAS

AF:

0.0931

Gnomad FIN

AF:

0.268

Gnomad MID

AF:

0.457

Gnomad NFE

AF:

0.319

Gnomad OTH

AF:

0.266

GnomAD2 exomes

AF:

0.221

AC:

37402

AN:

169442

AF XY:

0.223

show subpopulations

Gnomad AFR exome

AF:

0.0509

Gnomad AMR exome

AF:

0.128

Gnomad ASJ exome

AF:

0.406

Gnomad EAS exome

AF:

0.00137

Gnomad FIN exome

AF:

0.265

Gnomad NFE exome

AF:

0.314

Gnomad OTH exome

AF:

0.291

GnomAD4 exome

AF:

0.288

AC:

311631

AN:

1083212

Hom.:

33433

Cov.:

AF XY:

0.286

AC XY:

100069

AN XY:

350490

show subpopulations

African (AFR)

AF:

0.0526

AC:

1374

AN:

26113

American (AMR)

AF:

0.135

AC:

4691

AN:

34694

Ashkenazi Jewish (ASJ)

AF:

0.404

AC:

7779

AN:

19269

East Asian (EAS)

AF:

0.000964

AC:

AN:

30092

South Asian (SAS)

AF:

0.120

AC:

6385

AN:

53142

European-Finnish (FIN)

AF:

0.269

AC:

10779

AN:

40103

Middle Eastern (MID)

AF:

0.408

AC:

1664

AN:

4076

European-Non Finnish (NFE)

AF:

0.321

AC:

266056

AN:

830114

Other (OTH)

AF:

0.282

AC:

12874

AN:

45609

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

8558

17116

25673

34231

42789

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

8996

17992

26988

35984

44980

<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:

0.219

AC:

24454

AN:

111837

Hom.:

2609

Cov.:

AF XY:

0.207

AC XY:

7062

AN XY:

34065

show subpopulations

African (AFR)

AF:

0.0557

AC:

1719

AN:

30882

American (AMR)

AF:

0.196

AC:

2085

AN:

10615

Ashkenazi Jewish (ASJ)

AF:

0.405

AC:

1069

AN:

2638

East Asian (EAS)

AF:

0.00280

AC:

AN:

3572

South Asian (SAS)

AF:

0.0941

AC:

255

AN:

2710

European-Finnish (FIN)

AF:

0.268

AC:

1617

AN:

6032

Middle Eastern (MID)

AF:

0.465

AC:

AN:

213

European-Non Finnish (NFE)

AF:

0.319

AC:

16884

AN:

52981

Other (OTH)

AF:

0.264

AC:

401

AN:

1517

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

664

1327

1991

2654

3318

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

246

492

738

984

1230

<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:

0.214

Hom.:

1815

Bravo

AF:

0.208

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Jun 14, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

not specified

Benign:1

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

X-linked intellectual disability with marfanoid habitus

Benign:1

Sep 05, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

FG syndrome 1

Benign:1

Sep 05, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Blepharophimosis - intellectual disability syndrome, MKB type

Benign:1

Sep 05, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.58

CADD

Benign

(source)

DANN

Benign

0.73

PhyloP100

0.38

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

Details are displayed if max score is > 0.2

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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