rs62609586

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_005120.3(MED12):c.736-8A>C variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.282 in 1,204,692 control chromosomes in the GnomAD database, including 36,280 homozygotes. There are 109,353 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.22 ( 2627 hom., 6916 hem., cov: 23)

Exomes 𝑓: 0.29 ( 33653 hom. 102437 hem. )

Consequence

MED12
NM_005120.3 splice_region, splice_polypyrimidine_tract, intron

Scores

Splicing: ADA: 0.00002525

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: -0.413

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.86).

BP6

Variant X-71121319-A-C is Benign according to our data. Variant chrX-71121319-A-C is described in ClinVar as [Benign]. Clinvar id is 95257.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-71121319-A-C is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.315 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MED12	NM_005120.3 linkuse as main transcript	c.736-8A>C		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000374080.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MED12	ENST00000374080.8 linkuse as main transcript	c.736-8A>C		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_005120.3	P4	Q93074-1

Frequencies

GnomAD3 genomes

AF:

0.222

AC:

24609

AN:

110724

Hom.:

2629

Cov.:

AF XY:

0.210

AC XY:

6906

AN XY:

32956

show subpopulations

Gnomad AFR

AF:

0.0690

Gnomad AMI

AF:

0.470

Gnomad AMR

AF:

0.194

Gnomad ASJ

AF:

0.405

Gnomad EAS

AF:

0.00281

Gnomad SAS

AF:

0.0955

Gnomad FIN

AF:

0.259

Gnomad MID

AF:

0.470

Gnomad NFE

AF:

0.319

Gnomad OTH

AF:

0.269

GnomAD3 exomes

AF:

0.225

AC:

40789

AN:

181546

Hom.:

3776

AF XY:

0.231

AC XY:

15567

AN XY:

67404

show subpopulations

Gnomad AFR exome

AF:

0.0645

Gnomad AMR exome

AF:

0.129

Gnomad ASJ exome

AF:

0.405

Gnomad EAS exome

AF:

0.00140

Gnomad SAS exome

AF:

0.111

Gnomad FIN exome

AF:

0.267

Gnomad NFE exome

AF:

0.317

Gnomad OTH exome

AF:

0.293

GnomAD4 exome

AF:

0.288

AC:

315087

AN:

1093912

Hom.:

33653

Cov.:

AF XY:

0.285

AC XY:

102437

AN XY:

359640

show subpopulations

Gnomad4 AFR exome

AF:

0.0674

Gnomad4 AMR exome

AF:

0.136

Gnomad4 ASJ exome

AF:

0.403

Gnomad4 EAS exome

AF:

0.000961

Gnomad4 SAS exome

AF:

0.120

Gnomad4 FIN exome

AF:

0.270

Gnomad4 NFE exome

AF:

0.320

Gnomad4 OTH exome

AF:

0.284

GnomAD4 genome

AF:

0.222

AC:

24608

AN:

110780

Hom.:

2627

Cov.:

AF XY:

0.209

AC XY:

6916

AN XY:

33022

show subpopulations

Gnomad4 AFR

AF:

0.0691

Gnomad4 AMR

AF:

0.193

Gnomad4 ASJ

AF:

0.405

Gnomad4 EAS

AF:

0.00282

Gnomad4 SAS

AF:

0.0966

Gnomad4 FIN

AF:

0.259

Gnomad4 NFE

AF:

0.319

Gnomad4 OTH

AF:

0.267

Alfa

AF:

0.281

Hom.:

2760

Bravo

AF:

0.213

EpiCase

AF:

0.340

EpiControl

AF:

0.342

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 14, 2014	- -
Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

X-linked intellectual disability with marfanoid habitus

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Sep 05, 2021

- -

FG syndrome 1

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Sep 05, 2021

- -

FG syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Blepharophimosis - intellectual disability syndrome, MKB type

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Sep 05, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.86

Cadd

Benign

1.1

Dann

Benign

0.60

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000025

dbscSNV1_RF

Benign

0.0

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over