X-71140829-G-GGCAGCA

Variant names:

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP3BP6BS1BS2

The ENST00000374080.8(MED12):c.6253_6258dupCAGCAG(p.Gln2085_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 0.0000276 in 1,197,125 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 7 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: 0.000025 ( 0 hom. 6 hem. )

Consequence

MED12
ENST00000374080.8 conservative_inframe_insertion

Scores

Not classified

Clinical Significance

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

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: Benign. The variant received -10 ACMG points.

BP3

Nonframeshift variant in repetitive region in ENST00000374080.8

BP6

Variant X-71140829-G-GGCAGCA is Benign according to our data. Variant chrX-71140829-G-GGCAGCA is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 1208502.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0000564 (6/106331) while in subpopulation NFE AF = 0.000117 (6/51307). AF 95% confidence interval is 0.0000509. There are 0 homozygotes in GnomAd4. There are 1 alleles in the male GnomAd4 subpopulation. Median coverage is 22. This position passed quality control check.

BS2

High Hemizygotes in GnomAdExome4 at 6 XL gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000374080.8. 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.6253_6258dupCAGCAG	p.Gln2085_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.6253_6258dupCAGCAG	p.Gln2085_Gln2086dup	conservative_inframe_insertion	Exon 42 of 45	ENSP00000363193.3
MED12	ENST00000374102.6	TSL:1	c.6262_6267dupCAGCAG	p.Gln2088_Gln2089dup	conservative_inframe_insertion	Exon 42 of 45	ENSP00000363215.2
MED12	ENST00000690145.1		c.6259_6264dupCAGCAG	p.Gln2087_Gln2088dup	conservative_inframe_insertion	Exon 42 of 45	ENSP00000508818.1

Frequencies

GnomAD3 genomes

AF:

0.0000564

AC:

AN:

106331

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000117

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.0000248

AC:

AN:

1090794

Hom.:

Cov.:

AF XY:

0.0000167

AC XY:

AN XY:

358834

show subpopulations

African (AFR)

AF:

0.0000380

AC:

AN:

26320

American (AMR)

AF:

0.00

AC:

AN:

35021

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19257

East Asian (EAS)

AF:

0.00

AC:

AN:

30085

South Asian (SAS)

AF:

0.00

AC:

AN:

53752

European-Finnish (FIN)

AF:

0.00

AC:

AN:

37346

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4119

European-Non Finnish (NFE)

AF:

0.0000310

AC:

AN:

839057

Other (OTH)

AF:

0.00

AC:

AN:

45837

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.480

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:

106331

Hom.:

Cov.:

AF XY:

0.0000333

AC XY:

AN XY:

30049

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

29108

American (AMR)

AF:

0.00

AC:

AN:

9870

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2581

East Asian (EAS)

AF:

0.00

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:

0.000117

AC:

AN:

51307

Other (OTH)

AF:

0.00

AC:

AN:

1389

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

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:

0.00

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

FG syndrome (1)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

0.24

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