X-71132767-CCTCTTCTCTTCTCTTCTCTTCTCTTCTCTTCTCTTCTCTTCTCTT-CCTCTTCTCTTCTCTTCTCTTCTCTTCTCTTCTCTTCTCTTCTCTTCTCTTCTCTT

Variant names:

• chrX-71132767-C-CCTCTTCTCTT
• rs56658066
• NM_005120.3:c.4416-25_4416-16dupCTTCTCTTCT

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.4416-25_4416-16dupCTTCTCTTCT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0462 in 560,442 control chromosomes in the GnomAD database, including 1,355 homozygotes. There are 8,629 hemizygotes in GnomAD. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.055 (228 hom., 587 hem., cov: 0)
  • Exomes 𝑓: 0.046 (1355 hom. 8629 hem.)
  • Failed GnomAD Quality Control
• Consequence: MED12 NM_005120.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.294
• 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-C-CCTCTTCTCTT is Benign according to our data. Variant chrX-71132767-C-CCTCTTCTCTT is described in CliVar as Benign. Clinvar id is 804026.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-71132767-C-CCTCTTCTCTT is described in CliVar as Benign. Clinvar id is 804026.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-71132767-C-CCTCTTCTCTT is described in CliVar as Benign. Clinvar id is 804026.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-71132767-C-CCTCTTCTCTT is described in CliVar as Benign. Clinvar id is 804026.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-71132767-C-CCTCTTCTCTT is described in CliVar as Benign. Clinvar id is 804026.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-71132767-C-CCTCTTCTCTT is described in CliVar as Benign. Clinvar id is 804026.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-71132767-C-CCTCTTCTCTT is described in CliVar as Benign. Clinvar id is 804026.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-71132767-C-CCTCTTCTCTT is described in CliVar as Benign. Clinvar id is 804026.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-71132767-C-CCTCTTCTCTT is described in CliVar as Benign. Clinvar id is 804026.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-71132767-C-CCTCTTCTCTT is described in CliVar as Benign. Clinvar id is 804026.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-71132767-C-CCTCTTCTCTT is described in CliVar as Benign. Clinvar id is 804026.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-71132767-C-CCTCTTCTCTT is described in CliVar as Benign. Clinvar id is 804026.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-71132767-C-CCTCTTCTCTT is described in CliVar as Benign. Clinvar id is 804026.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-71132767-C-CCTCTTCTCTT is described in CliVar as Benign. Clinvar id is 804026.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAdExome4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.109 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MED12	NM_005120.3	c.4416-25_4416-16dupCTTCTCTTCT		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.4416-78_4416-77insCTCTTCTCTT		intron_variant	Intron 31 of 44	1	NM_005120.3	ENSP00000363193.3

Frequencies

GnomAD3 genomes AF: 0.0550 AC: 4983 AN: 90554 Hom.: 229 Cov.: 0

Gnomad AFR AF: 0.0368

Gnomad AMI AF: 0.00666

Gnomad AMR AF: 0.0360

Gnomad ASJ AF: 0.0674

Gnomad EAS AF: 0.121

Gnomad SAS AF: 0.0711

Gnomad FIN AF: 0.0384

Gnomad MID AF: 0.0667

Gnomad NFE AF: 0.0655

Gnomad OTH AF: 0.0488

GnomAD4 exome AF: 0.0462 AC: 25873 AN: 560442 Hom.: 1355 AF XY: 0.0534 AC XY: 8629 AN XY: 161592

African (AFR) AF: 0.0277 AC: 409 AN: 14790

American (AMR) AF: 0.0338 AC: 727 AN: 21536

Ashkenazi Jewish (ASJ) AF: 0.0571 AC: 807 AN: 14142

East Asian (EAS) AF: 0.113 AC: 2603 AN: 23126

South Asian (SAS) AF: 0.0818 AC: 2795 AN: 34174

European-Finnish (FIN) AF: 0.0477 AC: 1589 AN: 33334

Middle Eastern (MID) AF: 0.0549 AC: 105 AN: 1913

European-Non Finnish (NFE) AF: 0.0393 AC: 15326 AN: 390198

Other (OTH) AF: 0.0555 AC: 1512 AN: 27229

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.0550 AC: 4984 AN: 90594 Hom.: 228 Cov.: 0 AF XY: 0.0313 AC XY: 587 AN XY: 18744

African (AFR) AF: 0.0369 AC: 907 AN: 24610

American (AMR) AF: 0.0359 AC: 290 AN: 8070

Ashkenazi Jewish (ASJ) AF: 0.0674 AC: 156 AN: 2315

East Asian (EAS) AF: 0.120 AC: 308 AN: 2567

South Asian (SAS) AF: 0.0715 AC: 115 AN: 1608

European-Finnish (FIN) AF: 0.0384 AC: 147 AN: 3832

Middle Eastern (MID) AF: 0.0741 AC: 14 AN: 189

European-Non Finnish (NFE) AF: 0.0655 AC: 2985 AN: 45594

Other (OTH) AF: 0.0480 AC: 58 AN: 1208

Alfa AF: 0.0449 Hom.: 352

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

FG syndrome 1 Benign:1

May 28, 2019

Mendelics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

Nov 14, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.29
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;