chrX-71140829-G-GGCA

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP3BP6BS2

The NM_005120.3(MED12):c.6256_6258dupCAG(p.Gln2086dup) variant causes a conservative inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000376 in 1,197,107 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 10 hemizygotes in GnomAD. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000056 ( 0 hom., 1 hem., cov: 22)

Exomes 𝑓: 0.000036 ( 0 hom. 9 hem. )

Consequence

MED12
NM_005120.3 conservative_inframe_insertion

Scores

Not classified

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:5

Conservation

PhyloP100: 0.241

Publications

1 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: Likely_benign. The variant received -6 ACMG points.

BP3

Nonframeshift variant in repetitive region in NM_005120.3

BP6

Variant X-71140829-G-GGCA is Benign according to our data. Variant chrX-71140829-G-GGCA is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 166876.

BS2

High Hemizygotes in GnomAdExome4 at 9 XL gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005120.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MED12	NM_005120.3	MANE Select	c.6256_6258dupCAG	p.Gln2086dup	conservative_inframe_insertion	Exon 42 of 45	NP_005111.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
MED12	ENST00000374080.8	TSL:1 MANE Select	c.6256_6258dupCAG	p.Gln2086dup	conservative_inframe_insertion	Exon 42 of 45	ENSP00000363193.3
MED12	ENST00000374102.6	TSL:1	c.6265_6267dupCAG	p.Gln2089dup	conservative_inframe_insertion	Exon 42 of 45	ENSP00000363215.2
MED12	ENST00000690145.1		c.6262_6264dupCAG	p.Gln2088dup	conservative_inframe_insertion	Exon 42 of 45	ENSP00000508818.1

Frequencies

GnomAD3 genomes

AF:

0.0000564

AC:

AN:

106330

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000344

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000308

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000585

Gnomad OTH

AF:

0.000720

GnomAD2 exomes

AF:

0.0000631

AC:

AN:

158393

AF XY:

0.0000182

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000803

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000165

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000708

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000358

AC:

AN:

1090777

Hom.:

Cov.:

AF XY:

0.0000251

AC XY:

AN XY:

358817

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26320

American (AMR)

AF:

0.0000571

AC:

AN:

35019

Ashkenazi Jewish (ASJ)

AF:

0.0000519

AC:

AN:

19256

East Asian (EAS)

AF:

0.000133

AC:

AN:

30084

South Asian (SAS)

AF:

0.000130

AC:

AN:

53752

European-Finnish (FIN)

AF:

0.00

AC:

AN:

37346

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4118

European-Non Finnish (NFE)

AF:

0.0000274

AC:

AN:

839045

Other (OTH)

AF:

0.0000436

AC:

AN:

45837

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.470

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<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:

0.0000564

AC:

AN:

106330

Hom.:

Cov.:

AF XY:

0.0000333

AC XY:

AN XY:

30048

show subpopulations

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.0000344

AC:

AN:

29108

American (AMR)

AF:

0.00

AC:

AN:

9869

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2581

East Asian (EAS)

AF:

0.000308

AC:

AN:

3244

South Asian (SAS)

AF:

0.00

AC:

AN:

2409

European-Finnish (FIN)

AF:

0.00

AC:

AN:

5573

Middle Eastern (MID)

AF:

0.00

AC:

AN:

195

European-Non Finnish (NFE)

AF:

0.0000585

AC:

AN:

51307

Other (OTH)

AF:

0.000720

AC:

AN:

1389

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.00192603), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.395

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<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:

0.0000868

Hom.:

Bravo

AF:

0.0000302

ClinVar

ClinVar submissions as Germline

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (2)

Familial thoracic aortic aneurysm and aortic dissection (1)

FG syndrome (1)

FG syndrome 1 (1)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

0.24

Mutation Taster

=77/23

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over