X-71132767-CCTCTTCTCTTCTCTTCTCTTCTCTTCTCTTCTCTTCTCTTCTCTT-CCTCTTCTCTTCTCTTCTCTTCTCTTCTCTTCTCTTCTCTTCTCTTCTCTT

Variant names:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP6BA1

The NM_005120.3(MED12):c.4416-20_4416-16dupCTTCT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.101 in 645,426 control chromosomes in the GnomAD database, including 3,995 homozygotes. There are 14,901 hemizygotes in GnomAD. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.13 ( 911 hom., 1504 hem., cov: 0)

Exomes 𝑓: 0.096 ( 3084 hom. 13397 hem. )

Consequence

MED12
NM_005120.3 intron

Scores

Not classified

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:1

Conservation

PhyloP100: -0.294

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 -9 ACMG points.

BP6

Variant X-71132767-C-CCTCTT is Benign according to our data. Variant chrX-71132767-C-CCTCTT is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 95250. Variant chrX-71132767-C-CCTCTT is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 95250. Variant chrX-71132767-C-CCTCTT is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 95250. Variant chrX-71132767-C-CCTCTT is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 95250. Variant chrX-71132767-C-CCTCTT is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 95250. Variant chrX-71132767-C-CCTCTT is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 95250. Variant chrX-71132767-C-CCTCTT is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 95250. Variant chrX-71132767-C-CCTCTT is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 95250. Variant chrX-71132767-C-CCTCTT is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 95250. Variant chrX-71132767-C-CCTCTT is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 95250. Variant chrX-71132767-C-CCTCTT is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 95250. Variant chrX-71132767-C-CCTCTT is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 95250. Variant chrX-71132767-C-CCTCTT is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 95250. Variant chrX-71132767-C-CCTCTT is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 95250.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.227 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MED12	NM_005120.3 link	c.4416-20_4416-16dupCTTCT		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.4416-78_4416-77insCTCTT		intron_variant	Intron 31 of 44	1	NM_005120.3	ENSP00000363193.3		Q93074-1

Frequencies

GnomAD3 genomes

AF:

0.134

AC:

12102

AN:

90401

Hom.:

910

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0807

Gnomad AMI

AF:

0.211

Gnomad AMR

AF:

0.124

Gnomad ASJ

AF:

0.110

Gnomad EAS

AF:

0.243

Gnomad SAS

AF:

0.164

Gnomad FIN

AF:

0.133

Gnomad MID

AF:

0.120

Gnomad NFE

AF:

0.157

Gnomad OTH

AF:

0.130

GnomAD4 exome

AF:

0.0956

AC:

53064

AN:

554984

Hom.:

3084

AF XY:

0.0853

AC XY:

13397

AN XY:

157100

show subpopulations

African (AFR)

AF:

0.0541

AC:

798

AN:

14739

American (AMR)

AF:

0.102

AC:

2172

AN:

21361

Ashkenazi Jewish (ASJ)

AF:

0.0779

AC:

1095

AN:

14049

East Asian (EAS)

AF:

0.217

AC:

4924

AN:

22722

South Asian (SAS)

AF:

0.135

AC:

4505

AN:

33336

European-Finnish (FIN)

AF:

0.154

AC:

5059

AN:

32794

Middle Eastern (MID)

AF:

0.0965

AC:

183

AN:

1897

European-Non Finnish (NFE)

AF:

0.0813

AC:

31464

AN:

387085

Other (OTH)

AF:

0.106

AC:

2864

AN:

27001

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.433

Heterozygous variant carriers

1212

2424

3635

4847

6059

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

214

428

642

856

1070

<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:

0.134

AC:

12094

AN:

90442

Hom.:

911

Cov.:

AF XY:

0.0804

AC XY:

1504

AN XY:

18704

show subpopulations

African (AFR)

AF:

0.0805

AC:

1979

AN:

24579

American (AMR)

AF:

0.124

AC:

998

AN:

8058

Ashkenazi Jewish (ASJ)

AF:

0.110

AC:

254

AN:

2313

East Asian (EAS)

AF:

0.243

AC:

623

AN:

2562

South Asian (SAS)

AF:

0.164

AC:

263

AN:

1604

European-Finnish (FIN)

AF:

0.133

AC:

509

AN:

3815

Middle Eastern (MID)

AF:

0.111

AC:

AN:

189

European-Non Finnish (NFE)

AF:

0.157

AC:

7165

AN:

45513

Other (OTH)

AF:

0.128

AC:

155

AN:

1208

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.465

Heterozygous variant carriers

352

704

1055

1407

1759

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

114

228

342

456

570

<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:

0.134

Hom.:

352

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:1

May 14, 2014

Eurofins Ntd Llc (ga)

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Nov 19, 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

-0.29

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