X-71132767-CCTCTTCTCTTCTCTTCTCTTCTCTTCTCTTCTCTTCTCTTCTCTT-CCTCTTCTCTTCTCTTCTCTTCTCTTCTCTTCTCTTCTCTTCTCTTCTCTTCTCTTCTCTT

Variant names:

• chrX-71132767-C-CCTCTTCTCTTCTCTT
• rs56658066
• NM_005120.3:c.4416-30_4416-16dupCTTCTCTTCTCTTCT

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_Moderate BS1 BS2

The NM_005120.3(MED12):​c.4416-30_4416-16dupCTTCTCTTCTCTTCT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0204 in 561,748 control chromosomes in the GnomAD database, including 308 homozygotes. There are 3,721 hemizygotes in GnomAD. 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. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.021 (36 hom., 243 hem., cov: 0)
  • Exomes 𝑓: 0.020 (308 hom. 3721 hem.)
  • Failed GnomAD Quality Control
• Consequence: MED12 NM_005120.3 intron
• Clinical Significance: Benign criteria provided, single submitter 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: 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: 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-C-CCTCTTCTCTTCTCTT is Benign according to our data. Variant chrX-71132767-C-CCTCTTCTCTTCTCTT is described in ClinVar as Benign. ClinVar VariationId is 1221738.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population eas. GnomAdExome4 allele frequency = 0.0204 (11461/561748) while in subpopulation EAS AF = 0.0434 (1010/23247). AF 95% confidence interval is 0.0412. There are 308 homozygotes in GnomAdExome4. There are 3721 alleles in the male GnomAdExome4 subpopulation. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 308 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.4416-30_4416-16dupCTTCTCTTCTCTTCT		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_4416-77insCTCTTCTCTTCTCTT		intron	N/A	ENSP00000363193.3	Q93074-1
	MED12	ENST00000374102.6	TSL:1	c.4416-78_4416-77insCTCTTCTCTTCTCTT		intron	N/A	ENSP00000363215.2	Q93074-2
	MED12	ENST00000938012.1		c.4458-78_4458-77insCTCTTCTCTTCTCTT		intron	N/A	ENSP00000608071.1

Frequencies

GnomAD3 genomes AF: 0.0213 AC: 1930 AN: 90611 Hom.: 36 Cov.: 0

Gnomad AFR AF: 0.00562

Gnomad AMI AF: 0.00832

Gnomad AMR AF: 0.0189

Gnomad ASJ AF: 0.0168

Gnomad EAS AF: 0.0415

Gnomad SAS AF: 0.0210

Gnomad FIN AF: 0.0431

Gnomad MID AF: 0.0143

Gnomad NFE AF: 0.0276

Gnomad OTH AF: 0.0227

GnomAD4 exome AF: 0.0204 AC: 11461 AN: 561748 Hom.: 308 AF XY: 0.0229 AC XY: 3721 AN XY: 162530

African (AFR) AF: 0.00493 AC: 73 AN: 14809

American (AMR) AF: 0.0132 AC: 285 AN: 21557

Ashkenazi Jewish (ASJ) AF: 0.0165 AC: 234 AN: 14170

East Asian (EAS) AF: 0.0434 AC: 1010 AN: 23247

South Asian (SAS) AF: 0.0267 AC: 921 AN: 34437

European-Finnish (FIN) AF: 0.0559 AC: 1861 AN: 33310

Middle Eastern (MID) AF: 0.0261 AC: 50 AN: 1918

European-Non Finnish (NFE) AF: 0.0164 AC: 6403 AN: 391003

Other (OTH) AF: 0.0229 AC: 624 AN: 27297

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.0213 AC: 1928 AN: 90651 Hom.: 36 Cov.: 0 AF XY: 0.0130 AC XY: 243 AN XY: 18747

African (AFR) AF: 0.00560 AC: 138 AN: 24625

American (AMR) AF: 0.0188 AC: 152 AN: 8076

Ashkenazi Jewish (ASJ) AF: 0.0168 AC: 39 AN: 2315

East Asian (EAS) AF: 0.0416 AC: 107 AN: 2570

South Asian (SAS) AF: 0.0205 AC: 33 AN: 1610

European-Finnish (FIN) AF: 0.0431 AC: 165 AN: 3832

Middle Eastern (MID) AF: 0.0106 AC: 2 AN: 189

European-Non Finnish (NFE) AF: 0.0276 AC: 1260 AN: 45623

Other (OTH) AF: 0.0223 AC: 27 AN: 1210

Alfa AF: 0.0260 Hom.: 352

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

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

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs56658066;

hg19: chrX-70352617;