X-71132767-CCTCTTCTCTTCTCTTCTCTTCTCTTCTCTTCTCTTCTCTTCTCTT-CCTCTTCTCTTCTCTTCTCTTCTCTTCTCTTCTCTT

Variant names:

Variant summary

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

The NM_005120.3(MED12):c.4416-25_4416-16delCTTCTCTTCT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0168 in 652,215 control chromosomes in the GnomAD database, including 230 homozygotes. There are 2,887 hemizygotes in GnomAD. Variant has been reported in ClinVar as Likely benign (no stars).

Frequency

Genomes: 𝑓 0.042 ( 118 hom., 582 hem., cov: 0)

Exomes 𝑓: 0.013 ( 112 hom. 2305 hem. )

Consequence

MED12
NM_005120.3 intron

Scores

Not classified

Clinical Significance

Likely benign no assertion criteria provided B:1

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 -9 ACMG points.

BP6

Variant X-71132767-CCTCTTCTCTT-C is Benign according to our data. Variant chrX-71132767-CCTCTTCTCTT-C is described in CliVar as Likely_benign. Clinvar id is 3055527.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chrX-71132767-CCTCTTCTCTT-C is described in CliVar as Likely_benign. Clinvar id is 3055527.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chrX-71132767-CCTCTTCTCTT-C is described in CliVar as Likely_benign. Clinvar id is 3055527.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chrX-71132767-CCTCTTCTCTT-C is described in CliVar as Likely_benign. Clinvar id is 3055527.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chrX-71132767-CCTCTTCTCTT-C is described in CliVar as Likely_benign. Clinvar id is 3055527.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chrX-71132767-CCTCTTCTCTT-C is described in CliVar as Likely_benign. Clinvar id is 3055527.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chrX-71132767-CCTCTTCTCTT-C is described in CliVar as Likely_benign. Clinvar id is 3055527.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chrX-71132767-CCTCTTCTCTT-C is described in CliVar as Likely_benign. Clinvar id is 3055527.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chrX-71132767-CCTCTTCTCTT-C is described in CliVar as Likely_benign. Clinvar id is 3055527.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chrX-71132767-CCTCTTCTCTT-C is described in CliVar as Likely_benign. Clinvar id is 3055527.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chrX-71132767-CCTCTTCTCTT-C is described in CliVar as Likely_benign. Clinvar id is 3055527.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chrX-71132767-CCTCTTCTCTT-C is described in CliVar as Likely_benign. Clinvar id is 3055527.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chrX-71132767-CCTCTTCTCTT-C is described in CliVar as Likely_benign. Clinvar id is 3055527.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chrX-71132767-CCTCTTCTCTT-C is described in CliVar as Likely_benign. Clinvar id is 3055527.Status of the report is no_assertion_criteria_provided, 0 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.098 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MED12	NM_005120.3 link	c.4416-25_4416-16delCTTCTCTTCT		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_4416-68delCTCTTCTCTT		intron_variant	Intron 31 of 44	1	NM_005120.3	ENSP00000363193.3		Q93074-1

Frequencies

GnomAD3 genomes

AF:

0.0419

AC:

3796

AN:

90594

Hom.:

117

Cov.:

show subpopulations

Gnomad AFR

AF:

0.101

Gnomad AMI

AF:

0.00666

Gnomad AMR

AF:

0.0444

Gnomad ASJ

AF:

0.0337

Gnomad EAS

AF:

0.0190

Gnomad SAS

AF:

0.0148

Gnomad FIN

AF:

0.00261

Gnomad MID

AF:

0.0190

Gnomad NFE

AF:

0.0161

Gnomad OTH

AF:

0.0403

GnomAD4 exome

AF:

0.0127

AC:

7152

AN:

561581

Hom.:

112

AF XY:

0.0142

AC XY:

2305

AN XY:

162117

show subpopulations

African (AFR)

AF:

0.0727

AC:

1070

AN:

14723

American (AMR)

AF:

0.0269

AC:

579

AN:

21514

Ashkenazi Jewish (ASJ)

AF:

0.0292

AC:

414

AN:

14167

East Asian (EAS)

AF:

0.0192

AC:

445

AN:

23218

South Asian (SAS)

AF:

0.0180

AC:

619

AN:

34441

European-Finnish (FIN)

AF:

0.00327

AC:

109

AN:

33366

Middle Eastern (MID)

AF:

0.0187

AC:

AN:

1920

European-Non Finnish (NFE)

AF:

0.00848

AC:

3317

AN:

390933

Other (OTH)

AF:

0.0206

AC:

563

AN:

27299

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.494

Heterozygous variant carriers

197

394

591

788

985

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

144

192

240

<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:

0.0419

AC:

3799

AN:

90634

Hom.:

118

Cov.:

AF XY:

0.0311

AC XY:

582

AN XY:

18740

show subpopulations

African (AFR)

AF:

0.101

AC:

2492

AN:

24603

American (AMR)

AF:

0.0444

AC:

358

AN:

8072

Ashkenazi Jewish (ASJ)

AF:

0.0337

AC:

AN:

2313

East Asian (EAS)

AF:

0.0191

AC:

AN:

2570

South Asian (SAS)

AF:

0.0149

AC:

AN:

1610

European-Finnish (FIN)

AF:

0.00261

AC:

AN:

3833

Middle Eastern (MID)

AF:

0.0212

AC:

AN:

189

European-Non Finnish (NFE)

AF:

0.0161

AC:

733

AN:

45633

Other (OTH)

AF:

0.0388

AC:

AN:

1210

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.494

Heterozygous variant carriers

131

262

394

525

656

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

132

176

220

<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:

0.00

Hom.:

352

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

MED12-related disorder

Benign:1

Oct 30, 2020

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

0.31

Mutation Taster

=100/0

polymorphism

(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