X-71132767-CCTCTTCTCTTCTCTTCTCTTCTCTTCTCTTCTCTTCTCTTCTCTT-CCTCTTCTCTTCTCTTCTCTTCTCTTCTCTTCTCTT

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP6 BA1

The NM_005120.3(MED12):​c.4416-25_4416-16delCTTCTCTTCT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0168 in 652,215 control chromosomes in the GnomAD database, including 230 homozygotes. There are 2,887 hemizygotes in GnomAD. Variant has been reported in ClinVar as Likely benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.042 (118 hom., 582 hem., cov: 0)
  • Exomes 𝑓: 0.013 (112 hom. 2305 hem.)
• Consequence: MED12 NM_005120.3 intron
• Clinical Significance: Likely benign no assertion criteria provided B:1
• 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: G2P, Labcorp Genetics (formerly Invitae), 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: Orphanet, Labcorp Genetics (formerly Invitae), G2P
• blepharophimosis - intellectual disability syndrome, MKB type

  Inheritance: XL Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae)
• 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 -9 ACMG points.

• BP6: Variant X-71132767-CCTCTTCTCTT-C is Benign according to our data. Variant chrX-71132767-CCTCTTCTCTT-C is described in ClinVar as Likely_benign. ClinVar VariationId is 3055527.Status of the report is no_assertion_criteria_provided, 0 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.098 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005120.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MED12	NM_005120.3	MANE Select	c.4416-25_4416-16delCTTCTCTTCT		intron	N/A	NP_005111.2	Q93074-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MED12	ENST00000374080.8	TSL:1 MANE Select	c.4416-77_4416-68delCTCTTCTCTT		intron	N/A	ENSP00000363193.3	Q93074-1
	MED12	ENST00000374102.6	TSL:1	c.4416-77_4416-68delCTCTTCTCTT		intron	N/A	ENSP00000363215.2	Q93074-2
	MED12	ENST00000938012.1		c.4458-77_4458-68delCTCTTCTCTT		intron	N/A	ENSP00000608071.1

Frequencies

GnomAD3 genomes AF: 0.0419 AC: 3796 AN: 90594 Hom.: 117 Cov.: 0

Gnomad AFR AF: 0.101

Gnomad AMI AF: 0.00666

Gnomad AMR AF: 0.0444

Gnomad ASJ AF: 0.0337

Gnomad EAS AF: 0.0190

Gnomad SAS AF: 0.0148

Gnomad FIN AF: 0.00261

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.0161

Gnomad OTH AF: 0.0403

GnomAD4 exome AF: 0.0127 AC: 7152 AN: 561581 Hom.: 112 AF XY: 0.0142 AC XY: 2305 AN XY: 162117

African (AFR) AF: 0.0727 AC: 1070 AN: 14723

American (AMR) AF: 0.0269 AC: 579 AN: 21514

Ashkenazi Jewish (ASJ) AF: 0.0292 AC: 414 AN: 14167

East Asian (EAS) AF: 0.0192 AC: 445 AN: 23218

South Asian (SAS) AF: 0.0180 AC: 619 AN: 34441

European-Finnish (FIN) AF: 0.00327 AC: 109 AN: 33366

Middle Eastern (MID) AF: 0.0187 AC: 36 AN: 1920

European-Non Finnish (NFE) AF: 0.00848 AC: 3317 AN: 390933

Other (OTH) AF: 0.0206 AC: 563 AN: 27299

GnomAD4 genome AF: 0.0419 AC: 3799 AN: 90634 Hom.: 118 Cov.: 0 AF XY: 0.0311 AC XY: 582 AN XY: 18740

African (AFR) AF: 0.101 AC: 2492 AN: 24603

American (AMR) AF: 0.0444 AC: 358 AN: 8072

Ashkenazi Jewish (ASJ) AF: 0.0337 AC: 78 AN: 2313

East Asian (EAS) AF: 0.0191 AC: 49 AN: 2570

South Asian (SAS) AF: 0.0149 AC: 24 AN: 1610

European-Finnish (FIN) AF: 0.00261 AC: 10 AN: 3833

Middle Eastern (MID) AF: 0.0212 AC: 4 AN: 189

European-Non Finnish (NFE) AF: 0.0161 AC: 733 AN: 45633

Other (OTH) AF: 0.0388 AC: 47 AN: 1210

Alfa AF: 0.00 Hom.: 352

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	-	1	MED12-related disorder (1)

Computational scores

Source: dbNSFP v4.9

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

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;