X-71132767-CCTCTTCTCTTCTCTTCTCTTCTCTTCTCTTCTCTTCTCTTCTCTT-CCTCTTCTCTTCTCTTCTCTTCTCTTCTCTTCTCTTCTCTTCTCTTCTCTT

Variant names:

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

Variant summary

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

The NM_005120.3(MED12):​c.4416-20_4416-16dupCTTCT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.101 in 645,426 control chromosomes in the GnomAD database, including 3,995 homozygotes. There are 14,901 hemizygotes in GnomAD. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.13 (911 hom., 1504 hem., cov: 0)
  • Exomes 𝑓: 0.096 (3084 hom. 13397 hem.)
• Consequence: MED12 NM_005120.3 intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• 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 -9 ACMG points.

• BP6: Variant X-71132767-C-CCTCTT is Benign according to our data. Variant chrX-71132767-C-CCTCTT is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 95250.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.227 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.4416-20_4416-16dupCTTCT		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_4416-77insCTCTT		intron	N/A	ENSP00000363193.3	Q93074-1
	MED12	ENST00000374102.6	TSL:1	c.4416-78_4416-77insCTCTT		intron	N/A	ENSP00000363215.2	Q93074-2
	MED12	ENST00000938012.1		c.4458-78_4458-77insCTCTT		intron	N/A	ENSP00000608071.1

Frequencies

GnomAD3 genomes AF: 0.134 AC: 12102 AN: 90401 Hom.: 910 Cov.: 0

Gnomad AFR AF: 0.0807

Gnomad AMI AF: 0.211

Gnomad AMR AF: 0.124

Gnomad ASJ AF: 0.110

Gnomad EAS AF: 0.243

Gnomad SAS AF: 0.164

Gnomad FIN AF: 0.133

Gnomad MID AF: 0.120

Gnomad NFE AF: 0.157

Gnomad OTH AF: 0.130

GnomAD4 exome AF: 0.0956 AC: 53064 AN: 554984 Hom.: 3084 AF XY: 0.0853 AC XY: 13397 AN XY: 157100

African (AFR) AF: 0.0541 AC: 798 AN: 14739

American (AMR) AF: 0.102 AC: 2172 AN: 21361

Ashkenazi Jewish (ASJ) AF: 0.0779 AC: 1095 AN: 14049

East Asian (EAS) AF: 0.217 AC: 4924 AN: 22722

South Asian (SAS) AF: 0.135 AC: 4505 AN: 33336

European-Finnish (FIN) AF: 0.154 AC: 5059 AN: 32794

Middle Eastern (MID) AF: 0.0965 AC: 183 AN: 1897

European-Non Finnish (NFE) AF: 0.0813 AC: 31464 AN: 387085

Other (OTH) AF: 0.106 AC: 2864 AN: 27001

GnomAD4 genome AF: 0.134 AC: 12094 AN: 90442 Hom.: 911 Cov.: 0 AF XY: 0.0804 AC XY: 1504 AN XY: 18704

African (AFR) AF: 0.0805 AC: 1979 AN: 24579

American (AMR) AF: 0.124 AC: 998 AN: 8058

Ashkenazi Jewish (ASJ) AF: 0.110 AC: 254 AN: 2313

East Asian (EAS) AF: 0.243 AC: 623 AN: 2562

South Asian (SAS) AF: 0.164 AC: 263 AN: 1604

European-Finnish (FIN) AF: 0.133 AC: 509 AN: 3815

Middle Eastern (MID) AF: 0.111 AC: 21 AN: 189

European-Non Finnish (NFE) AF: 0.157 AC: 7165 AN: 45513

Other (OTH) AF: 0.128 AC: 155 AN: 1208

Alfa AF: 0.134 Hom.: 352

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	1	not provided (2)

Computational scores

Source: dbNSFP v4.9

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;