17-61946978-C-G

Variant names:

• chr17-61946978-C-G
• NM_005121.3:c.6331G>C

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_005121.3(MED13):​c.6331G>C​(p.Glu2111Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: MED13 NM_005121.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.51
• Publications: 0 publications found

Genes affected

MED13 (HGNC:22474): (mediator complex subunit 13) This gene encodes a component of the mediator complex (also known as TRAP, SMCC, DRIP, or ARC), a transcriptional coactivator complex thought to be required for the expression of almost all genes. The mediator complex is recruited by transcriptional activators or nuclear receptors to induce gene expression, possibly by interacting with RNA polymerase II and promoting the formation of a transcriptional pre-initiation complex. The product of this gene is proposed to form a sub-complex with MED12, cyclin C, and CDK8 that can negatively regulate transactivation by mediator. [provided by RefSeq, Jul 2008]

MED13 Gene-Disease associations (from GenCC):

• complex neurodevelopmental disorder

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• intellectual developmental disorder 61

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Illumina, G2P, Ambry Genetics
• syndromic intellectual disability

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005121.3. 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
	MED13	NM_005121.3	MANE Select	c.6331G>C	p.Glu2111Gln	missense	Exon 29 of 30	NP_005112.2	Q9UHV7

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MED13	ENST00000397786.7	TSL:1 MANE Select	c.6331G>C	p.Glu2111Gln	missense	Exon 29 of 30	ENSP00000380888.2	Q9UHV7
	MED13	ENST00000934727.1		c.6172G>C	p.Glu2058Gln	missense	Exon 28 of 29	ENSP00000604786.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.68
BayesDel_addAF	Uncertain	0.087	D
BayesDel_noAF	Benign	-0.11
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.56	D
Eigen	Pathogenic	0.80
Eigen_PC	Pathogenic	0.77
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D
M_CAP	Uncertain	0.091	D
MetaRNN	Uncertain	0.53	D
MetaSVM	Uncertain	0.37	D
MutationAssessor	Uncertain	2.5	M
PhyloP100		7.5
PrimateAI	Pathogenic	0.88	D
PROVEAN	Benign	-2.3	N
REVEL	Uncertain	0.43
Sift	Uncertain	0.0050	D
Sift4G	Uncertain	0.0070	D
Polyphen		1.0	D
Vest4		0.58
MutPred		0.20		Loss of catalytic residue at E2111 (P = 0.1429)
MVP		0.63
MPC		2.0
ClinPred		0.95	D
GERP RS		5.3
Varity_R		0.50
gMVP		0.47

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

hg19: chr17-60024339; COSMIC: COSV101181018;