chrX-71132767-CCTCTTCTCTTCTCTTCTCTTCTCTT-C

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_Moderate BA1

The NM_005120.3(MED12):​c.4416-40_4416-16delCTTCTCTTCTCTTCTCTTCTCTTCT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.054 in 653,221 control chromosomes in the GnomAD database, including 1,214 homozygotes. There are 12,437 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 0.085 (344 hom., 1698 hem., cov: 0)
  • Exomes 𝑓: 0.049 (870 hom. 10739 hem.)
• Consequence: MED12 NM_005120.3 intron
• Clinical Significance: Benign criteria provided, single submitter 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: 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 -10 ACMG points.

• BP6: Variant X-71132767-CCTCTTCTCTTCTCTTCTCTTCTCTT-C is Benign according to our data. Variant chrX-71132767-CCTCTTCTCTTCTCTTCTCTTCTCTT-C is described in ClinVar as Benign. ClinVar VariationId is 213614.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.189 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.4416-40_4416-16delCTTCTCTTCTCTTCTCTTCTCTTCT		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_4416-53delCTCTTCTCTTCTCTTCTCTTCTCTT		intron	N/A	ENSP00000363193.3	Q93074-1
	MED12	ENST00000374102.6	TSL:1	c.4416-77_4416-53delCTCTTCTCTTCTCTTCTCTTCTCTT		intron	N/A	ENSP00000363215.2	Q93074-2
	MED12	ENST00000938012.1		c.4458-77_4458-53delCTCTTCTCTTCTCTTCTCTTCTCTT		intron	N/A	ENSP00000608071.1

Frequencies

GnomAD3 genomes AF: 0.0853 AC: 7723 AN: 90564 Hom.: 340 Cov.: 0

Gnomad AFR AF: 0.153

Gnomad AMI AF: 0.0166

Gnomad AMR AF: 0.0457

Gnomad ASJ AF: 0.0259

Gnomad EAS AF: 0.144

Gnomad SAS AF: 0.207

Gnomad FIN AF: 0.0303

Gnomad MID AF: 0.0524

Gnomad NFE AF: 0.0570

Gnomad OTH AF: 0.0824

GnomAD4 exome AF: 0.0489 AC: 27538 AN: 562616 Hom.: 870 AF XY: 0.0659 AC XY: 10739 AN XY: 162986

African (AFR) AF: 0.106 AC: 1569 AN: 14795

American (AMR) AF: 0.0245 AC: 529 AN: 21582

Ashkenazi Jewish (ASJ) AF: 0.0224 AC: 318 AN: 14202

East Asian (EAS) AF: 0.111 AC: 2583 AN: 23304

South Asian (SAS) AF: 0.162 AC: 5599 AN: 34524

European-Finnish (FIN) AF: 0.0279 AC: 934 AN: 33462

Middle Eastern (MID) AF: 0.0583 AC: 112 AN: 1920

European-Non Finnish (NFE) AF: 0.0364 AC: 14255 AN: 391475

Other (OTH) AF: 0.0599 AC: 1639 AN: 27352

GnomAD4 genome AF: 0.0854 AC: 7742 AN: 90605 Hom.: 344 Cov.: 0 AF XY: 0.0908 AC XY: 1698 AN XY: 18707

African (AFR) AF: 0.153 AC: 3762 AN: 24595

American (AMR) AF: 0.0456 AC: 368 AN: 8072

Ashkenazi Jewish (ASJ) AF: 0.0259 AC: 60 AN: 2315

East Asian (EAS) AF: 0.144 AC: 370 AN: 2565

South Asian (SAS) AF: 0.208 AC: 334 AN: 1607

European-Finnish (FIN) AF: 0.0303 AC: 116 AN: 3834

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

European-Non Finnish (NFE) AF: 0.0570 AC: 2599 AN: 45617

Other (OTH) AF: 0.0934 AC: 113 AN: 1210

Alfa AF: 0.0285 Hom.: 352

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

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;