rs12849277

chrX-71132797-T-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BP6_Very_Strong

The NM_005120.3(MED12):c.4416-48T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000288 in 69,531 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.000029 (0 hom., 0 hem., cov: 14)
  • Exomes 𝑓: 0.010 (5 hom. 19 hem.)
  • Failed GnomAD Quality Control
• Consequence: MED12 NM_005120.3 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.29

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]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.93).
• BP6: Variant X-71132797-T-C is Benign according to our data. Variant chrX-71132797-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 259638.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MED12	NM_005120.3	c.4416-48T>C		intron_variant		ENST00000374080.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MED12	ENST00000374080.8	c.4416-48T>C		intron_variant		1	NM_005120.3	P4

Frequencies

GnomAD3 genomes AF: 0.0000288 AC: 2 AN: 69531 Hom.: 0 Cov.: 14 AF XY: 0.00 AC XY: 0 AN XY: 22577

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: 0.000296

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000381

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00111 AC: 83 AN: 74474 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 29534

Gnomad AFR exome AF: 0.000368

Gnomad AMR exome AF: 0.000794

Gnomad ASJ exome AF: 0.00385

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000431

Gnomad FIN exome AF: 0.000575

Gnomad NFE exome AF: 0.00208

Gnomad OTH exome AF: 0.00107

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0105 AC: 4029 AN: 384255 Hom.: 5 Cov.: 6 AF XY: 0.000154 AC XY: 19 AN XY: 123733

Gnomad4 AFR exome AF: 0.00189

Gnomad4 AMR exome AF: 0.00318

Gnomad4 ASJ exome AF: 0.00727

Gnomad4 EAS exome AF: 0.0000400

Gnomad4 SAS exome AF: 0.000986

Gnomad4 FIN exome AF: 0.000774

Gnomad4 NFE exome AF: 0.0153

Gnomad4 OTH exome AF: 0.00791

GnomAD4 genome AF: 0.0000288 AC: 2 AN: 69531 Hom.: 0 Cov.: 14 AF XY: 0.00 AC XY: 0 AN XY: 22577

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000296

Gnomad4 NFE AF: 0.0000381

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0175 Hom.: 49

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Nov 20, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
Cadd	Benign	0.13
Dann	Benign	0.45

Splicing

Name	Calibrated prediction	Score	Prediction
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

Other links and lift over

dbSNP: rs12849277; hg19: chrX-70352647; COSMIC: COSV100380659; COSMIC: COSV100380659;