X-71141265-GCAGCAA-GCAGCAACAGCAA
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Variant summary
Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP3BP6BS1BS2
The NM_005120.3(MED12):c.6315_6320dupACAGCA(p.Gln2106_Gln2107dup) variant causes a disruptive inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000101 in 108,870 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 2 hemizygotes in GnomAD. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.00010 ( 0 hom., 2 hem., cov: 23)
Exomes 𝑓: 0.000018 ( 0 hom. 4 hem. )
Failed GnomAD Quality Control
Consequence
MED12
NM_005120.3 disruptive_inframe_insertion
NM_005120.3 disruptive_inframe_insertion
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 2.20
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]
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ACMG classification
Classification made for transcript
Verdict is Benign. Variant got -10 ACMG points.
BP3
Nonframeshift variant in repetitive region in NM_005120.3
BP6
Variant X-71141265-G-GCAGCAA is Benign according to our data. Variant chrX-71141265-G-GCAGCAA is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 445536.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=2}.
BS1
Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000101 (11/108870) while in subpopulation AFR AF= 0.000268 (8/29801). AF 95% confidence interval is 0.000133. There are 0 homozygotes in gnomad4. There are 2 alleles in male gnomad4 subpopulation. Median coverage is 23. This position pass quality control queck.
BS2
High Hemizygotes in GnomAd4 at 2 XL gene
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.000101 AC: 11AN: 108870Hom.: 0 Cov.: 23 AF XY: 0.0000633 AC XY: 2AN XY: 31608
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GnomAD3 exomes AF: 0.0000440 AC: 5AN: 113583Hom.: 0 AF XY: 0.0000246 AC XY: 1AN XY: 40659
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GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000181 AC: 19AN: 1050407Hom.: 0 Cov.: 32 AF XY: 0.0000117 AC XY: 4AN XY: 341563
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Data not reliable, filtered out with message: AS_VQSR
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GnomAD4 genome AF: 0.000101 AC: 11AN: 108870Hom.: 0 Cov.: 23 AF XY: 0.0000633 AC XY: 2AN XY: 31608
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:1Benign:2
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
FG syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Dec 31, 2024 | This variant, c.6315_6320dup, results in the insertion of 2 amino acid(s) of the MED12 protein (p.Gln2114_Gln2115dup), but otherwise preserves the integrity of the reading frame. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has not been reported in the literature in individuals affected with MED12-related conditions. Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
Familial thoracic aortic aneurysm and aortic dissection Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | May 11, 2021 | This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. - |
not provided Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics | Jun 15, 2017 | - - |
Computational scores
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Find out detailed SpliceAI scores and Pangolin per-transcript scores at