X-71132767-CCTCTTCTCTTCTCTTCTCTTCTCTTCTCTTCTCTTCTCTTCTCTT-CCTCTTCTCTTCTCTT

Variant names:

• chrX-71132767-CCTCTTCTCTTCTCTTCTCTTCTCTTCTCTT-C
• rs56658066
• NM_005120.3:c.4416-45_4416-16delCTTCTCTTCTCTTCTCTTCTCTTCTCTTCT

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_005120.3(MED12):​c.4416-45_4416-16delCTTCTCTTCTCTTCTCTTCTCTTCTCTTCT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.219 in 562,359 control chromosomes in the GnomAD database, including 15,649 homozygotes. There are 39,234 hemizygotes in GnomAD. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.25 (2582 hom., 5311 hem., cov: 0)
  • Exomes 𝑓: 0.22 (15649 hom. 39234 hem.)
  • Failed GnomAD Quality Control
• Consequence: MED12 NM_005120.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.312
• Publications: 3 publications found

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 Gene-Disease associations (from GenCC):

• FG syndrome 1

  Inheritance: XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), G2P, Orphanet
• MED12-related intellectual disability syndrome

  Inheritance: XL Classification: DEFINITIVE Submitted by: ClinGen
• X-linked intellectual disability with marfanoid habitus

  Inheritance: XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), G2P, Orphanet
• blepharophimosis - intellectual disability syndrome, MKB type

  Inheritance: XL Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet
• cholestasis-pigmentary retinopathy-cleft palate syndrome

  Inheritance: XL Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)

ENSG00000228427 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -16 ACMG points.

• BP6: Variant X-71132767-CCTCTTCTCTTCTCTTCTCTTCTCTTCTCTT-C is Benign according to our data. Variant chrX-71132767-CCTCTTCTCTTCTCTTCTCTTCTCTTCTCTT-C is described in CliVar as Benign. Clinvar id is 95251.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-71132767-CCTCTTCTCTTCTCTTCTCTTCTCTTCTCTT-C is described in CliVar as Benign. Clinvar id is 95251.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-71132767-CCTCTTCTCTTCTCTTCTCTTCTCTTCTCTT-C is described in CliVar as Benign. Clinvar id is 95251.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-71132767-CCTCTTCTCTTCTCTTCTCTTCTCTTCTCTT-C is described in CliVar as Benign. Clinvar id is 95251.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-71132767-CCTCTTCTCTTCTCTTCTCTTCTCTTCTCTT-C is described in CliVar as Benign. Clinvar id is 95251.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-71132767-CCTCTTCTCTTCTCTTCTCTTCTCTTCTCTT-C is described in CliVar as Benign. Clinvar id is 95251.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-71132767-CCTCTTCTCTTCTCTTCTCTTCTCTTCTCTT-C is described in CliVar as Benign. Clinvar id is 95251.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-71132767-CCTCTTCTCTTCTCTTCTCTTCTCTTCTCTT-C is described in CliVar as Benign. Clinvar id is 95251.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-71132767-CCTCTTCTCTTCTCTTCTCTTCTCTTCTCTT-C is described in CliVar as Benign. Clinvar id is 95251.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-71132767-CCTCTTCTCTTCTCTTCTCTTCTCTTCTCTT-C is described in CliVar as Benign. Clinvar id is 95251.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-71132767-CCTCTTCTCTTCTCTTCTCTTCTCTTCTCTT-C is described in CliVar as Benign. Clinvar id is 95251.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-71132767-CCTCTTCTCTTCTCTTCTCTTCTCTTCTCTT-C is described in CliVar as Benign. Clinvar id is 95251.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-71132767-CCTCTTCTCTTCTCTTCTCTTCTCTTCTCTT-C is described in CliVar as Benign. Clinvar id is 95251.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-71132767-CCTCTTCTCTTCTCTTCTCTTCTCTTCTCTT-C is described in CliVar as Benign. Clinvar id is 95251.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAdExome4 highest subpopulation (MID) allele frequency at 95% confidence interval = 0.331 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MED12	NM_005120.3	c.4416-45_4416-16delCTTCTCTTCTCTTCTCTTCTCTTCTCTTCT		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_4416-48delCTCTTCTCTTCTCTTCTCTTCTCTTCTCTT		intron_variant	Intron 31 of 44	1	NM_005120.3	ENSP00000363193.3

Frequencies

GnomAD3 genomes AF: 0.251 AC: 22704 AN: 90438 Hom.: 2584 Cov.: 0

Gnomad AFR AF: 0.0814

Gnomad AMI AF: 0.417

Gnomad AMR AF: 0.219

Gnomad ASJ AF: 0.432

Gnomad EAS AF: 0.00426

Gnomad SAS AF: 0.116

Gnomad FIN AF: 0.323

Gnomad MID AF: 0.493

Gnomad NFE AF: 0.347

Gnomad OTH AF: 0.299

GnomAD4 exome AF: 0.219 AC: 122883 AN: 562359 Hom.: 15649 AF XY: 0.241 AC XY: 39234 AN XY: 162735

African (AFR) AF: 0.0595 AC: 881 AN: 14804

American (AMR) AF: 0.128 AC: 2759 AN: 21577

Ashkenazi Jewish (ASJ) AF: 0.358 AC: 5072 AN: 14182

East Asian (EAS) AF: 0.00275 AC: 64 AN: 23302

South Asian (SAS) AF: 0.119 AC: 4101 AN: 34524

European-Finnish (FIN) AF: 0.288 AC: 9615 AN: 33429

Middle Eastern (MID) AF: 0.353 AC: 676 AN: 1916

European-Non Finnish (NFE) AF: 0.238 AC: 93053 AN: 391286

Other (OTH) AF: 0.244 AC: 6662 AN: 27339

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.251 AC: 22700 AN: 90479 Hom.: 2582 Cov.: 0 AF XY: 0.286 AC XY: 5311 AN XY: 18593

African (AFR) AF: 0.0813 AC: 2001 AN: 24598

American (AMR) AF: 0.219 AC: 1767 AN: 8069

Ashkenazi Jewish (ASJ) AF: 0.432 AC: 997 AN: 2308

East Asian (EAS) AF: 0.00428 AC: 11 AN: 2570

South Asian (SAS) AF: 0.118 AC: 190 AN: 1608

European-Finnish (FIN) AF: 0.323 AC: 1234 AN: 3823

Middle Eastern (MID) AF: 0.505 AC: 95 AN: 188

European-Non Finnish (NFE) AF: 0.347 AC: 15801 AN: 45518

Other (OTH) AF: 0.297 AC: 358 AN: 1207

Alfa AF: 0.159 Hom.: 352

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Apr 23, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was found in TAADV2-WO-FBN1-PANCARD,TAADV2-PANCARD -

May 09, 2013

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.31
Mutation Taster		=100/0	polymorphism (auto)

Splicing

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

Other links and lift over

dbSNP: rs56658066; hg19: chrX-70352617;