chrX-71132767-C-CCTCTTCTCTTCTCTTCTCTTCTCTT

Variant names:

• chrX-71132767-C-CCTCTTCTCTTCTCTTCTCTTCTCTT
• rs56658066
• NM_005120.3:c.4416-40_4416-16dupCTTCTCTTCTCTTCTCTTCTCTTCT

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BS1 BS2

The NM_005120.3(MED12):​c.4416-40_4416-16dupCTTCTCTTCTCTTCTCTTCTCTTCT variant causes a intron change involving the alteration of a non-conserved nucleotide. It is difficult to determine the true allele frequency of this variant because it is of type INS_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0049 (5 hom., 38 hem., cov: 0)
  • Exomes 𝑓: 0.0045 (27 hom. 829 hem.)
  • Failed GnomAD Quality Control
• Consequence: MED12 NM_005120.3 intron
• Clinical Significance: Not reported in ClinVar
• 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: 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 -8 ACMG points.

• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0049 (444/90663) while in subpopulation NFE AF = 0.00635 (290/45635). AF 95% confidence interval is 0.00575. There are 5 homozygotes in GnomAd4. There are 38 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 5 XL gene

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.4416-40_4416-16dupCTTCTCTTCTCTTCTCTTCTCTTCT		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.4416-78_4416-77insCTCTTCTCTTCTCTTCTCTTCTCTT		intron	N/A	ENSP00000363193.3	Q93074-1
	MED12	ENST00000374102.6	TSL:1	c.4416-78_4416-77insCTCTTCTCTTCTCTTCTCTTCTCTT		intron	N/A	ENSP00000363215.2	Q93074-2
	MED12	ENST00000938012.1		c.4458-78_4458-77insCTCTTCTCTTCTCTTCTCTTCTCTT		intron	N/A	ENSP00000608071.1

Frequencies

GnomAD3 genomes AF: 0.00491 AC: 445 AN: 90623 Hom.: 5 Cov.: 0

Gnomad AFR AF: 0.00122

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00434

Gnomad ASJ AF: 0.00346

Gnomad EAS AF: 0.00581

Gnomad SAS AF: 0.00370

Gnomad FIN AF: 0.0149

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00635

Gnomad OTH AF: 0.00336

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00449 AC: 2525 AN: 562556 Hom.: 27 AF XY: 0.00508 AC XY: 829 AN XY: 163072

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.000878 AC: 13 AN: 14812

American (AMR) AF: 0.00663 AC: 143 AN: 21570

Ashkenazi Jewish (ASJ) AF: 0.00162 AC: 23 AN: 14196

East Asian (EAS) AF: 0.00322 AC: 75 AN: 23306

South Asian (SAS) AF: 0.00310 AC: 107 AN: 34532

European-Finnish (FIN) AF: 0.0181 AC: 604 AN: 33422

Middle Eastern (MID) AF: 0.00416 AC: 8 AN: 1921

European-Non Finnish (NFE) AF: 0.00365 AC: 1428 AN: 391439

Other (OTH) AF: 0.00453 AC: 124 AN: 27358

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.00490 AC: 444 AN: 90663 Hom.: 5 Cov.: 0 AF XY: 0.00203 AC XY: 38 AN XY: 18749

African (AFR) AF: 0.00122 AC: 30 AN: 24625

American (AMR) AF: 0.00421 AC: 34 AN: 8076

Ashkenazi Jewish (ASJ) AF: 0.00346 AC: 8 AN: 2315

East Asian (EAS) AF: 0.00584 AC: 15 AN: 2570

South Asian (SAS) AF: 0.00373 AC: 6 AN: 1610

European-Finnish (FIN) AF: 0.0149 AC: 57 AN: 3832

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 189

European-Non Finnish (NFE) AF: 0.00635 AC: 290 AN: 45635

Other (OTH) AF: 0.00331 AC: 4 AN: 1210

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.29
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;