X-71132767-CCTCTTCTCTTCTCTTCTCTTCTCTTCTCTTCTCTTCTCTTCTCTT-CCTCTTCTCTTCTCTTCTCTTCTCTTCTCTT

Variant names:

Variant summary

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

The NM_005120.3(MED12):c.4416-30_4416-16delCTTCTCTTCTCTTCT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00573 in 653,305 control chromosomes in the GnomAD database, including 126 homozygotes. There are 833 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 Likely benign (no stars).

Frequency

Genomes: 𝑓 0.024 ( 87 hom., 379 hem., cov: 0)

Exomes 𝑓: 0.0028 ( 39 hom. 454 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-CCTCTTCTCTTCTCTT-C is Benign according to our data. Variant chrX-71132767-CCTCTTCTCTTCTCTT-C is described in CliVar as Likely_benign. Clinvar id is 3059906.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chrX-71132767-CCTCTTCTCTTCTCTT-C is described in CliVar as Likely_benign. Clinvar id is 3059906.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chrX-71132767-CCTCTTCTCTTCTCTT-C is described in CliVar as Likely_benign. Clinvar id is 3059906.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chrX-71132767-CCTCTTCTCTTCTCTT-C is described in CliVar as Likely_benign. Clinvar id is 3059906.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chrX-71132767-CCTCTTCTCTTCTCTT-C is described in CliVar as Likely_benign. Clinvar id is 3059906.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chrX-71132767-CCTCTTCTCTTCTCTT-C is described in CliVar as Likely_benign. Clinvar id is 3059906.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chrX-71132767-CCTCTTCTCTTCTCTT-C is described in CliVar as Likely_benign. Clinvar id is 3059906.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chrX-71132767-CCTCTTCTCTTCTCTT-C is described in CliVar as Likely_benign. Clinvar id is 3059906.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chrX-71132767-CCTCTTCTCTTCTCTT-C is described in CliVar as Likely_benign. Clinvar id is 3059906.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chrX-71132767-CCTCTTCTCTTCTCTT-C is described in CliVar as Likely_benign. Clinvar id is 3059906.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chrX-71132767-CCTCTTCTCTTCTCTT-C is described in CliVar as Likely_benign. Clinvar id is 3059906.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chrX-71132767-CCTCTTCTCTTCTCTT-C is described in CliVar as Likely_benign. Clinvar id is 3059906.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chrX-71132767-CCTCTTCTCTTCTCTT-C is described in CliVar as Likely_benign. Clinvar id is 3059906.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chrX-71132767-CCTCTTCTCTTCTCTT-C is described in CliVar as Likely_benign. Clinvar id is 3059906.Status of the report is no_assertion_criteria_provided, 0 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0774 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MED12	NM_005120.3 link	c.4416-30_4416-16delCTTCTCTTCTCTTCT		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_4416-63delCTCTTCTCTTCTCTT		intron_variant	Intron 31 of 44	1	NM_005120.3	ENSP00000363193.3		Q93074-1

Frequencies

GnomAD3 genomes

AF:

0.0237

AC:

2145

AN:

90599

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0802

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00918

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00155

Gnomad SAS

AF:

0.00494

Gnomad FIN

AF:

0.000261

Gnomad MID

AF:

0.00476

Gnomad NFE

AF:

0.00151

Gnomad OTH

AF:

0.0168

GnomAD4 exome

AF:

0.00282

AC:

1589

AN:

562666

Hom.:

AF XY:

0.00278

AC XY:

454

AN XY:

163022

show subpopulations

African (AFR)

AF:

0.0552

AC:

816

AN:

14795

American (AMR)

AF:

0.00389

AC:

AN:

21579

Ashkenazi Jewish (ASJ)

AF:

0.000141

AC:

AN:

14196

East Asian (EAS)

AF:

0.000729

AC:

AN:

23304

South Asian (SAS)

AF:

0.00362

AC:

125

AN:

34534

European-Finnish (FIN)

AF:

0.000418

AC:

AN:

33467

Middle Eastern (MID)

AF:

0.00156

AC:

AN:

1922

European-Non Finnish (NFE)

AF:

0.000912

AC:

357

AN:

391514

Other (OTH)

AF:

0.00625

AC:

171

AN:

27355

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

148

197

246

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

<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:

0.0238

AC:

2155

AN:

90639

Hom.:

Cov.:

AF XY:

0.0202

AC XY:

379

AN XY:

18739

show subpopulations

African (AFR)

AF:

0.0804

AC:

1977

AN:

24601

American (AMR)

AF:

0.00929

AC:

AN:

8074

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2315

East Asian (EAS)

AF:

0.00156

AC:

AN:

2570

South Asian (SAS)

AF:

0.00497

AC:

AN:

1610

European-Finnish (FIN)

AF:

0.000261

AC:

AN:

3834

Middle Eastern (MID)

AF:

0.00529

AC:

AN:

189

European-Non Finnish (NFE)

AF:

0.00151

AC:

AN:

45635

Other (OTH)

AF:

0.0165

AC:

AN:

1210

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.507

Heterozygous variant carriers

148

221

295

369

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

120

<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

Nov 12, 2021

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