X-71140797-ACAG-ACAGCAGCAG

Position:

• chrX-71140797-ACAG-ACAGCAGCAG

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP3 BP6 BS2

The NM_005120.3(MED12):​c.6223_6228dupCAGCAG​(p.Gln2075_Gln2076dup) variant causes a conservative inframe insertion change. The variant allele was found at a frequency of 0.000182 in 109,909 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 3 hemizygotes in GnomAD. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00018 (0 hom., 3 hem., cov: 22)
  • Exomes 𝑓: 0.00030 (0 hom. 57 hem.)
  • Failed GnomAD Quality Control
• Consequence: MED12 NM_005120.3 conservative_inframe_insertion
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:4
• Conservation: PhyloP100: 4.36

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 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -6 ACMG points.

• BP3: Nonframeshift variant in repetitive region in NM_005120.3
• BP6: Variant X-71140797-A-ACAGCAG is Benign according to our data. Variant chrX-71140797-A-ACAGCAG is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 213619.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=1, Benign=2}.
• BS2: High Hemizygotes in GnomAd4 at 3 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MED12	NM_005120.3	c.6223_6228dupCAGCAG	p.Gln2075_Gln2076dup	conservative_inframe_insertion	42/45	ENST00000374080.8	NP_005111.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MED12	ENST00000374080.8	c.6223_6228dupCAGCAG	p.Gln2075_Gln2076dup	conservative_inframe_insertion	42/45	1	NM_005120.3	ENSP00000363193.3

Frequencies

GnomAD3 genomes AF: 0.000182 AC: 20 AN: 109909 Hom.: 0 Cov.: 22 AF XY: 0.0000923 AC XY: 3 AN XY: 32501

Gnomad AFR AF: 0.0000662

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: 0.000343

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000190 AC: 32 AN: 168423 Hom.: 0 AF XY: 0.000101 AC XY: 6 AN XY: 59581

Gnomad AFR exome AF: 0.0000853

Gnomad AMR exome AF: 0.0000762

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000773

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000740

Gnomad NFE exome AF: 0.000335

Gnomad OTH exome AF: 0.000473

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.000305 AC: 333 AN: 1091813 Hom.: 0 Cov.: 33 AF XY: 0.000159 AC XY: 57 AN XY: 359025

Gnomad4 AFR exome AF: 0.000152

Gnomad4 AMR exome AF: 0.0000570

Gnomad4 ASJ exome AF: 0.0000519

Gnomad4 EAS exome AF: 0.0000664

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000509

Gnomad4 NFE exome AF: 0.000376

Gnomad4 OTH exome AF: 0.000153

GnomAD4 genome AF: 0.000182 AC: 20 AN: 109909 Hom.: 0 Cov.: 22 AF XY: 0.0000923 AC XY: 3 AN XY: 32501

Gnomad4 AFR AF: 0.0000662

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000343

Gnomad4 OTH AF: 0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

History of neurodevelopmental disorder Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 16, 2010

- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Jul 28, 2016

- -

Familial thoracic aortic aneurysm and aortic dissection Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 28, 2017

This alteration is classified as 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

GeneDx

May 12, 2022

See Variant Classification Assertion Criteria. -

FG syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 25, 2024

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs757160341; hg19: chrX-70360647;