X-71132767-CCTCTTCTCTTCTCTTCTCTTCTCTTCTCTTCTCTTCTCTTCTCTT-CCTCTTCTCTTCTCTTCTCTT

Variant names:

• chrX-71132767-CCTCTTCTCTTCTCTTCTCTTCTCTT-C
• rs56658066
• NM_005120.3:c.4416-40_4416-16delCTTCTCTTCTCTTCTCTTCTCTTCT

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP6_Moderate BA1

The NM_005120.3(MED12):​c.4416-40_4416-16delCTTCTCTTCTCTTCTCTTCTCTTCT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.054 in 653,221 control chromosomes in the GnomAD database, including 1,214 homozygotes. There are 12,437 hemizygotes in GnomAD. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.085 (344 hom., 1698 hem., cov: 0)
  • Exomes 𝑓: 0.049 (870 hom. 10739 hem.)
• Consequence: MED12 NM_005120.3 intron
• Clinical Significance: Benign criteria provided, single submitter B:2
• Conservation: PhyloP100: 0.312

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 -10 ACMG points.

• BP6: Variant X-71132767-CCTCTTCTCTTCTCTTCTCTTCTCTT-C is Benign according to our data. Variant chrX-71132767-CCTCTTCTCTTCTCTTCTCTTCTCTT-C is described in ClinVar as [Benign]. Clinvar id is 213614.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.189 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MED12	NM_005120.3	c.4416-40_4416-16delCTTCTCTTCTCTTCTCTTCTCTTCT		intron_variant	Intron 31 of 44	ENST00000374080.8	NP_005111.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MED12	ENST00000374080.8	c.4416-77_4416-53delCTCTTCTCTTCTCTTCTCTTCTCTT		intron_variant	Intron 31 of 44	1	NM_005120.3	ENSP00000363193.3

Frequencies

GnomAD3 genomes AF: 0.0853 AC: 7723 AN: 90564 Hom.: 340 Cov.: 0 AF XY: 0.0903 AC XY: 1686 AN XY: 18666

Gnomad AFR AF: 0.153

Gnomad AMI AF: 0.0166

Gnomad AMR AF: 0.0457

Gnomad ASJ AF: 0.0259

Gnomad EAS AF: 0.144

Gnomad SAS AF: 0.207

Gnomad FIN AF: 0.0303

Gnomad MID AF: 0.0524

Gnomad NFE AF: 0.0570

Gnomad OTH AF: 0.0824

GnomAD4 exome AF: 0.0489 AC: 27538 AN: 562616 Hom.: 870 AF XY: 0.0659 AC XY: 10739 AN XY: 162986

Gnomad4 AFR exome AF: 0.106

Gnomad4 AMR exome AF: 0.0245

Gnomad4 ASJ exome AF: 0.0224

Gnomad4 EAS exome AF: 0.111

Gnomad4 SAS exome AF: 0.162

Gnomad4 FIN exome AF: 0.0279

Gnomad4 NFE exome AF: 0.0364

Gnomad4 OTH exome AF: 0.0599

GnomAD4 genome AF: 0.0854 AC: 7742 AN: 90605 Hom.: 344 Cov.: 0 AF XY: 0.0908 AC XY: 1698 AN XY: 18707

Gnomad4 AFR AF: 0.153

Gnomad4 AMR AF: 0.0456

Gnomad4 ASJ AF: 0.0259

Gnomad4 EAS AF: 0.144

Gnomad4 SAS AF: 0.208

Gnomad4 FIN AF: 0.0303

Gnomad4 NFE AF: 0.0570

Gnomad4 OTH AF: 0.0934

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Apr 24, 2015

GeneDx

Significance: Benign

Review Status: flagged submission

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

not provided Benign:1

Aug 15, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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: rs56658066; hg19: chrX-70352617;