X-71132767-CCTCTTCTCTTCTCTTCTCTTCTCTTCTCTTCTCTTCTCTTCTCTT-CCTCTTCTCTTCTCTTCTCTT

Variant names:

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_ModerateBA1

The NM_005120.3(MED12):c.4416-40_4416-16delCTTCTCTTCTCTTCTCTTCTCTTCT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.054 in 653,221 control chromosomes in the GnomAD database, including 1,214 homozygotes. There are 12,437 hemizygotes in GnomAD. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.085 ( 344 hom., 1698 hem., cov: 0)

Exomes 𝑓: 0.049 ( 870 hom. 10739 hem. )

Consequence

MED12
NM_005120.3 intron

Scores

Not classified

Clinical Significance

Benign criteria provided, single submitter B:2

Conservation

PhyloP100: 0.312

Publications

3 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 -10 ACMG points.

BP6

Variant X-71132767-CCTCTTCTCTTCTCTTCTCTTCTCTT-C is Benign according to our data. Variant chrX-71132767-CCTCTTCTCTTCTCTTCTCTTCTCTT-C is described in CliVar as Benign. Clinvar id is 213614.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-71132767-CCTCTTCTCTTCTCTTCTCTTCTCTT-C is described in CliVar as Benign. Clinvar id is 213614.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-71132767-CCTCTTCTCTTCTCTTCTCTTCTCTT-C is described in CliVar as Benign. Clinvar id is 213614.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-71132767-CCTCTTCTCTTCTCTTCTCTTCTCTT-C is described in CliVar as Benign. Clinvar id is 213614.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-71132767-CCTCTTCTCTTCTCTTCTCTTCTCTT-C is described in CliVar as Benign. Clinvar id is 213614.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-71132767-CCTCTTCTCTTCTCTTCTCTTCTCTT-C is described in CliVar as Benign. Clinvar id is 213614.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-71132767-CCTCTTCTCTTCTCTTCTCTTCTCTT-C is described in CliVar as Benign. Clinvar id is 213614.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-71132767-CCTCTTCTCTTCTCTTCTCTTCTCTT-C is described in CliVar as Benign. Clinvar id is 213614.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-71132767-CCTCTTCTCTTCTCTTCTCTTCTCTT-C is described in CliVar as Benign. Clinvar id is 213614.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-71132767-CCTCTTCTCTTCTCTTCTCTTCTCTT-C is described in CliVar as Benign. Clinvar id is 213614.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-71132767-CCTCTTCTCTTCTCTTCTCTTCTCTT-C is described in CliVar as Benign. Clinvar id is 213614.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-71132767-CCTCTTCTCTTCTCTTCTCTTCTCTT-C is described in CliVar as Benign. Clinvar id is 213614.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-71132767-CCTCTTCTCTTCTCTTCTCTTCTCTT-C is described in CliVar as Benign. Clinvar id is 213614.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-71132767-CCTCTTCTCTTCTCTTCTCTTCTCTT-C is described in CliVar as Benign. Clinvar id is 213614.Status of the report is criteria_provided_single_submitter, 1 stars.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.189 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MED12	NM_005120.3 link	c.4416-40_4416-16delCTTCTCTTCTCTTCTCTTCTCTTCT		intron_variant	Intron 31 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.4416-77_4416-53delCTCTTCTCTTCTCTTCTCTTCTCTT		intron_variant	Intron 31 of 44	1	NM_005120.3	ENSP00000363193.3		Q93074-1

Frequencies

GnomAD3 genomes

AF:

0.0853

AC:

7723

AN:

90564

Hom.:

340

Cov.:

show subpopulations

Gnomad AFR

AF:

0.153

Gnomad AMI

AF:

0.0166

Gnomad AMR

AF:

0.0457

Gnomad ASJ

AF:

0.0259

Gnomad EAS

AF:

0.144

Gnomad SAS

AF:

0.207

Gnomad FIN

AF:

0.0303

Gnomad MID

AF:

0.0524

Gnomad NFE

AF:

0.0570

Gnomad OTH

AF:

0.0824

GnomAD4 exome

AF:

0.0489

AC:

27538

AN:

562616

Hom.:

870

AF XY:

0.0659

AC XY:

10739

AN XY:

162986

show subpopulations

African (AFR)

AF:

0.106

AC:

1569

AN:

14795

American (AMR)

AF:

0.0245

AC:

529

AN:

21582

Ashkenazi Jewish (ASJ)

AF:

0.0224

AC:

318

AN:

14202

East Asian (EAS)

AF:

0.111

AC:

2583

AN:

23304

South Asian (SAS)

AF:

0.162

AC:

5599

AN:

34524

European-Finnish (FIN)

AF:

0.0279

AC:

934

AN:

33462

Middle Eastern (MID)

AF:

0.0583

AC:

112

AN:

1920

European-Non Finnish (NFE)

AF:

0.0364

AC:

14255

AN:

391475

Other (OTH)

AF:

0.0599

AC:

1639

AN:

27352

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.556

Heterozygous variant carriers

641

1282

1924

2565

3206

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

234

468

702

936

1170

<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:

0.0854

AC:

7742

AN:

90605

Hom.:

344

Cov.:

AF XY:

0.0908

AC XY:

1698

AN XY:

18707

show subpopulations

African (AFR)

AF:

0.153

AC:

3762

AN:

24595

American (AMR)

AF:

0.0456

AC:

368

AN:

8072

Ashkenazi Jewish (ASJ)

AF:

0.0259

AC:

AN:

2315

East Asian (EAS)

AF:

0.144

AC:

370

AN:

2565

South Asian (SAS)

AF:

0.208

AC:

334

AN:

1607

European-Finnish (FIN)

AF:

0.0303

AC:

116

AN:

3834

Middle Eastern (MID)

AF:

0.0529

AC:

AN:

189

European-Non Finnish (NFE)

AF:

0.0570

AC:

2599

AN:

45617

Other (OTH)

AF:

0.0934

AC:

113

AN:

1210

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.531

Heterozygous variant carriers

234

467

701

934

1168

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

172

258

344

430

<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:

0.0285

Hom.:

352

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Benign:1

Apr 24, 2015

GeneDx

Significance:Benign

Review Status:flagged submission

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 provided

Benign:1

Aug 15, 2019

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

0.31

Mutation Taster

=100/0

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