X-71132767-CCTCTTCTCTTCTCTTCTCTTCTCTTCTCTTCTCTTCTCTTCTCTT-CCTCTTCTCTTCTCTTCTCTTCTCTTCTCTTCTCTTCTCTT

Variant names:

• chrX-71132767-CCTCTT-C
• rs56658066
• NM_005120.3:c.4416-20_4416-16delCTTCT

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.4416-20_4416-16delCTTCT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0798 in 651,266 control chromosomes in the GnomAD database, including 2,461 homozygotes. There are 14,295 hemizygotes in GnomAD. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.13 (780 hom., 1731 hem., cov: 0)
  • Exomes 𝑓: 0.072 (1681 hom. 12564 hem.)
• Consequence: MED12 NM_005120.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.0730
• 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-CCTCTT-C is Benign according to our data. Variant chrX-71132767-CCTCTT-C is described in CliVar as Benign. Clinvar id is 95249.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-71132767-CCTCTT-C is described in CliVar as Benign. Clinvar id is 95249.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-71132767-CCTCTT-C is described in CliVar as Benign. Clinvar id is 95249.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-71132767-CCTCTT-C is described in CliVar as Benign. Clinvar id is 95249.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-71132767-CCTCTT-C is described in CliVar as Benign. Clinvar id is 95249.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-71132767-CCTCTT-C is described in CliVar as Benign. Clinvar id is 95249.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-71132767-CCTCTT-C is described in CliVar as Benign. Clinvar id is 95249.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-71132767-CCTCTT-C is described in CliVar as Benign. Clinvar id is 95249.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-71132767-CCTCTT-C is described in CliVar as Benign. Clinvar id is 95249.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-71132767-CCTCTT-C is described in CliVar as Benign. Clinvar id is 95249.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-71132767-CCTCTT-C is described in CliVar as Benign. Clinvar id is 95249.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-71132767-CCTCTT-C is described in CliVar as Benign. Clinvar id is 95249.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-71132767-CCTCTT-C is described in CliVar as Benign. Clinvar id is 95249.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-71132767-CCTCTT-C is described in CliVar as Benign. Clinvar id is 95249.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.196 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MED12	NM_005120.3	c.4416-20_4416-16delCTTCT		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_4416-73delCTCTT		intron_variant	Intron 31 of 44	1	NM_005120.3	ENSP00000363193.3

Frequencies

GnomAD3 genomes AF: 0.130 AC: 11760 AN: 90423 Hom.: 784 Cov.: 0

Gnomad AFR AF: 0.201

Gnomad AMI AF: 0.0266

Gnomad AMR AF: 0.149

Gnomad ASJ AF: 0.0722

Gnomad EAS AF: 0.0970

Gnomad SAS AF: 0.0834

Gnomad FIN AF: 0.116

Gnomad MID AF: 0.0524

Gnomad NFE AF: 0.0981

Gnomad OTH AF: 0.128

GnomAD4 exome AF: 0.0717 AC: 40210 AN: 560804 Hom.: 1681 AF XY: 0.0777 AC XY: 12564 AN XY: 161782

African (AFR) AF: 0.153 AC: 2254 AN: 14739

American (AMR) AF: 0.158 AC: 3394 AN: 21475

Ashkenazi Jewish (ASJ) AF: 0.0663 AC: 939 AN: 14157

East Asian (EAS) AF: 0.124 AC: 2878 AN: 23203

South Asian (SAS) AF: 0.0739 AC: 2542 AN: 34403

European-Finnish (FIN) AF: 0.132 AC: 4398 AN: 33280

Middle Eastern (MID) AF: 0.0599 AC: 115 AN: 1919

European-Non Finnish (NFE) AF: 0.0548 AC: 21408 AN: 390346

Other (OTH) AF: 0.0836 AC: 2282 AN: 27282

GnomAD4 genome AF: 0.130 AC: 11757 AN: 90462 Hom.: 780 Cov.: 0 AF XY: 0.0925 AC XY: 1731 AN XY: 18706

African (AFR) AF: 0.201 AC: 4922 AN: 24537

American (AMR) AF: 0.149 AC: 1199 AN: 8061

Ashkenazi Jewish (ASJ) AF: 0.0722 AC: 167 AN: 2314

East Asian (EAS) AF: 0.0975 AC: 250 AN: 2565

South Asian (SAS) AF: 0.0815 AC: 131 AN: 1608

European-Finnish (FIN) AF: 0.116 AC: 443 AN: 3815

Middle Eastern (MID) AF: 0.0529 AC: 10 AN: 189

European-Non Finnish (NFE) AF: 0.0981 AC: 4468 AN: 45562

Other (OTH) AF: 0.125 AC: 151 AN: 1210

Alfa AF: 0.0667 Hom.: 352

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

May 01, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was found in TAADV2-PANCARD -

Nov 29, 2012

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		0.073
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;