X-71132767-CCTCTTCTCTTCTCTTCTCTTCTCTTCTCTTCTCTTCTCTTCTCTT-CCTCTTCTCTTCTCTTCTCTTCTCTTCTCTT

Variant names:

• chrX-71132767-CCTCTTCTCTTCTCTT-C
• rs56658066
• NM_005120.3:c.4416-30_4416-16delCTTCTCTTCTCTTCT

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP6 BA1

The NM_005120.3(MED12):​c.4416-30_4416-16delCTTCTCTTCTCTTCT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00573 in 653,305 control chromosomes in the GnomAD database, including 126 homozygotes. There are 833 hemizygotes in GnomAD. Variant has been reported in ClinVar as Likely benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.024 (87 hom., 379 hem., cov: 0)
  • Exomes 𝑓: 0.0028 (39 hom. 454 hem.)
• Consequence: MED12 NM_005120.3 intron
• Clinical Significance: Likely benign no assertion criteria provided B:1
• 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 -9 ACMG points.

• BP6: Variant X-71132767-CCTCTTCTCTTCTCTT-C is Benign according to our data. Variant chrX-71132767-CCTCTTCTCTTCTCTT-C is described in ClinVar as [Likely_benign]. Clinvar id is 3059906.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chrX-71132767-CCTCTTCTCTTCTCTT-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0774 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MED12	NM_005120.3	c.4416-30_4416-16delCTTCTCTTCTCTTCT		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_4416-63delCTCTTCTCTTCTCTT		intron_variant	Intron 31 of 44	1	NM_005120.3	ENSP00000363193.3

Frequencies

GnomAD3 genomes AF: 0.0237 AC: 2145 AN: 90599 Hom.: 86 Cov.: 0 AF XY: 0.0201 AC XY: 376 AN XY: 18699

Gnomad AFR AF: 0.0802

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00918

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00155

Gnomad SAS AF: 0.00494

Gnomad FIN AF: 0.000261

Gnomad MID AF: 0.00476

Gnomad NFE AF: 0.00151

Gnomad OTH AF: 0.0168

GnomAD4 exome AF: 0.00282 AC: 1589 AN: 562666 Hom.: 39 AF XY: 0.00278 AC XY: 454 AN XY: 163022

Gnomad4 AFR exome AF: 0.0552

Gnomad4 AMR exome AF: 0.00389

Gnomad4 ASJ exome AF: 0.000141

Gnomad4 EAS exome AF: 0.000729

Gnomad4 SAS exome AF: 0.00362

Gnomad4 FIN exome AF: 0.000418

Gnomad4 NFE exome AF: 0.000912

Gnomad4 OTH exome AF: 0.00625

GnomAD4 genome AF: 0.0238 AC: 2155 AN: 90639 Hom.: 87 Cov.: 0 AF XY: 0.0202 AC XY: 379 AN XY: 18739

Gnomad4 AFR AF: 0.0804

Gnomad4 AMR AF: 0.00929

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00156

Gnomad4 SAS AF: 0.00497

Gnomad4 FIN AF: 0.000261

Gnomad4 NFE AF: 0.00151

Gnomad4 OTH AF: 0.0165

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

Submissions by phenotype

MED12-related disorder Benign:1

Nov 12, 2021

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

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;