rs41298482

Variant names:

• chrX-71136854-C-T
• rs41298482
• NM_005120.3:c.5401-25C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_005120.3(MED12):​c.5401-25C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.126 in 1,208,219 control chromosomes in the GnomAD database, including 6,999 homozygotes. There are 50,986 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.15 (1079 hom., 4684 hem., cov: 22)
  • Exomes 𝑓: 0.12 (5920 hom. 46302 hem.)
• Consequence: MED12 NM_005120.3 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 1.98
• Publications: 4 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant X-71136854-C-T is Benign according to our data. Variant chrX-71136854-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 259639.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.232 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.5401-25C>T		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.5401-25C>T		intron	N/A	ENSP00000363193.3	Q93074-1
	MED12	ENST00000374102.6	TSL:1	c.5401-25C>T		intron	N/A	ENSP00000363215.2	Q93074-2
	MED12	ENST00000938012.1		c.5443-25C>T		intron	N/A	ENSP00000608071.1

Frequencies

GnomAD3 genomes AF: 0.151 AC: 16718 AN: 110808 Hom.: 1076 Cov.: 22

Gnomad AFR AF: 0.237

Gnomad AMI AF: 0.0247

Gnomad AMR AF: 0.111

Gnomad ASJ AF: 0.0909

Gnomad EAS AF: 0.128

Gnomad SAS AF: 0.212

Gnomad FIN AF: 0.107

Gnomad MID AF: 0.134

Gnomad NFE AF: 0.118

Gnomad OTH AF: 0.138

GnomAD2 exomes AF: 0.135 AC: 24178 AN: 179137 AF XY: 0.137

Gnomad AFR exome AF: 0.240

Gnomad AMR exome AF: 0.102

Gnomad ASJ exome AF: 0.0909

Gnomad EAS exome AF: 0.152

Gnomad FIN exome AF: 0.115

Gnomad NFE exome AF: 0.113

Gnomad OTH exome AF: 0.117

GnomAD4 exome AF: 0.124 AC: 135992 AN: 1097357 Hom.: 5920 Cov.: 33 AF XY: 0.128 AC XY: 46302 AN XY: 362885

African (AFR) AF: 0.239 AC: 6307 AN: 26392

American (AMR) AF: 0.102 AC: 3586 AN: 35173

Ashkenazi Jewish (ASJ) AF: 0.0913 AC: 1770 AN: 19383

East Asian (EAS) AF: 0.118 AC: 3557 AN: 30196

South Asian (SAS) AF: 0.223 AC: 12043 AN: 54114

European-Finnish (FIN) AF: 0.116 AC: 4646 AN: 40130

Middle Eastern (MID) AF: 0.121 AC: 499 AN: 4117

European-Non Finnish (NFE) AF: 0.116 AC: 97424 AN: 841785

Other (OTH) AF: 0.134 AC: 6160 AN: 46067

GnomAD4 genome AF: 0.151 AC: 16733 AN: 110862 Hom.: 1079 Cov.: 22 AF XY: 0.141 AC XY: 4684 AN XY: 33106

African (AFR) AF: 0.237 AC: 7184 AN: 30349

American (AMR) AF: 0.110 AC: 1151 AN: 10460

Ashkenazi Jewish (ASJ) AF: 0.0909 AC: 241 AN: 2650

East Asian (EAS) AF: 0.128 AC: 450 AN: 3516

South Asian (SAS) AF: 0.213 AC: 561 AN: 2631

European-Finnish (FIN) AF: 0.107 AC: 638 AN: 5948

Middle Eastern (MID) AF: 0.124 AC: 27 AN: 217

European-Non Finnish (NFE) AF: 0.118 AC: 6242 AN: 52899

Other (OTH) AF: 0.148 AC: 222 AN: 1505

Alfa AF: 0.131 Hom.: 1048

Bravo AF: 0.154

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	15
DANN	Benign	0.64
PhyloP100		2.0
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.19		Details are displayed if max score is > 0.2

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: rs41298482;

hg19: chrX-70356704;

COSMIC: COSV61332980;