X-71132767-CCTCTTCTCTTCTCTTCTCTTCTCTTCTCTTCTCTTCTCTTCTCTT-CCTCTTCTCTTCTCTTCTCTTCTCTTCTCTTCTCTTCTCTTCTCTTCTCTTCTCTTCTCTT

Variant names:

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_ModerateBS1BS2

The NM_005120.3(MED12):c.4416-30_4416-16dupCTTCTCTTCTCTTCT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0204 in 561,748 control chromosomes in the GnomAD database, including 308 homozygotes. There are 3,721 hemizygotes in GnomAD. It is difficult to determine the true allele frequency of this variant because it is of type INS_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 0.021 ( 36 hom., 243 hem., cov: 0)

Exomes 𝑓: 0.020 ( 308 hom. 3721 hem. )

Failed GnomAD Quality Control

Consequence

MED12
NM_005120.3 intron

Scores

Not classified

Clinical Significance

Benign criteria provided, single submitter B: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 -10 ACMG points.

BP6

Variant X-71132767-C-CCTCTTCTCTTCTCTT is Benign according to our data. Variant chrX-71132767-C-CCTCTTCTCTTCTCTT is described in CliVar as Benign. Clinvar id is 1221738.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-71132767-C-CCTCTTCTCTTCTCTT is described in CliVar as Benign. Clinvar id is 1221738.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-71132767-C-CCTCTTCTCTTCTCTT is described in CliVar as Benign. Clinvar id is 1221738.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-71132767-C-CCTCTTCTCTTCTCTT is described in CliVar as Benign. Clinvar id is 1221738.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-71132767-C-CCTCTTCTCTTCTCTT is described in CliVar as Benign. Clinvar id is 1221738.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-71132767-C-CCTCTTCTCTTCTCTT is described in CliVar as Benign. Clinvar id is 1221738.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-71132767-C-CCTCTTCTCTTCTCTT is described in CliVar as Benign. Clinvar id is 1221738.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-71132767-C-CCTCTTCTCTTCTCTT is described in CliVar as Benign. Clinvar id is 1221738.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-71132767-C-CCTCTTCTCTTCTCTT is described in CliVar as Benign. Clinvar id is 1221738.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-71132767-C-CCTCTTCTCTTCTCTT is described in CliVar as Benign. Clinvar id is 1221738.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-71132767-C-CCTCTTCTCTTCTCTT is described in CliVar as Benign. Clinvar id is 1221738.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-71132767-C-CCTCTTCTCTTCTCTT is described in CliVar as Benign. Clinvar id is 1221738.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-71132767-C-CCTCTTCTCTTCTCTT is described in CliVar as Benign. Clinvar id is 1221738.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-71132767-C-CCTCTTCTCTTCTCTT is described in CliVar as Benign. Clinvar id is 1221738.Status of the report is criteria_provided_single_submitter, 1 stars.

BS1

Variant frequency is greater than expected in population eas. GnomAdExome4 allele frequency = 0.0204 (11461/561748) while in subpopulation EAS AF = 0.0434 (1010/23247). AF 95% confidence interval is 0.0412. There are 308 homozygotes in GnomAdExome4. There are 3721 alleles in the male GnomAdExome4 subpopulation. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 308 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MED12	NM_005120.3 link	c.4416-30_4416-16dupCTTCTCTTCTCTTCT		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_4416-77insCTCTTCTCTTCTCTT		intron_variant	Intron 31 of 44	1	NM_005120.3	ENSP00000363193.3		Q93074-1

Frequencies

GnomAD3 genomes

AF:

0.0213

AC:

1930

AN:

90611

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00562

Gnomad AMI

AF:

0.00832

Gnomad AMR

AF:

0.0189

Gnomad ASJ

AF:

0.0168

Gnomad EAS

AF:

0.0415

Gnomad SAS

AF:

0.0210

Gnomad FIN

AF:

0.0431

Gnomad MID

AF:

0.0143

Gnomad NFE

AF:

0.0276

Gnomad OTH

AF:

0.0227

GnomAD4 exome

AF:

0.0204

AC:

11461

AN:

561748

Hom.:

308

AF XY:

0.0229

AC XY:

3721

AN XY:

162530

show subpopulations

African (AFR)

AF:

0.00493

AC:

AN:

14809

American (AMR)

AF:

0.0132

AC:

285

AN:

21557

Ashkenazi Jewish (ASJ)

AF:

0.0165

AC:

234

AN:

14170

East Asian (EAS)

AF:

0.0434

AC:

1010

AN:

23247

South Asian (SAS)

AF:

0.0267

AC:

921

AN:

34437

European-Finnish (FIN)

AF:

0.0559

AC:

1861

AN:

33310

Middle Eastern (MID)

AF:

0.0261

AC:

AN:

1918

European-Non Finnish (NFE)

AF:

0.0164

AC:

6403

AN:

391003

Other (OTH)

AF:

0.0229

AC:

624

AN:

27297

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.411

Heterozygous variant carriers

269

538

808

1077

1346

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

114

152

190

<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

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0213

AC:

1928

AN:

90651

Hom.:

Cov.:

AF XY:

0.0130

AC XY:

243

AN XY:

18747

show subpopulations

African (AFR)

AF:

0.00560

AC:

138

AN:

24625

American (AMR)

AF:

0.0188

AC:

152

AN:

8076

Ashkenazi Jewish (ASJ)

AF:

0.0168

AC:

AN:

2315

East Asian (EAS)

AF:

0.0416

AC:

107

AN:

2570

South Asian (SAS)

AF:

0.0205

AC:

AN:

1610

European-Finnish (FIN)

AF:

0.0431

AC:

165

AN:

3832

Middle Eastern (MID)

AF:

0.0106

AC:

AN:

189

European-Non Finnish (NFE)

AF:

0.0276

AC:

1260

AN:

45623

Other (OTH)

AF:

0.0223

AC:

AN:

1210

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.483

Heterozygous variant carriers

140

210

280

350

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome 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

Alfa

AF:

0.0260

Hom.:

352

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Benign:1

Nov 14, 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