9-133341516-C-T

Variant names:

• chr9-133341516-C-T
• rs587668796
• NM_133640.5:c.592G>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_133640.5(MED22):​c.592G>A​(p.Glu198Lys) variant causes a missense change. The variant allele was found at a frequency of 0.00000198 in 1,517,392 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000015 (0 hom.)
• Consequence: MED22 NM_133640.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.81
• Publications: 0 publications found

Genes affected

MED22 (HGNC:11477): (mediator complex subunit 22) This gene encodes a protein component of the mediator complex, which functions in the regulation of transcription by bridging interactions between gene-specific regulatory factors, RNA polymerase II, and general transcription factors. Alternatively spliced transcript variants encoding different isoforms have been observed. [provided by RefSeq, Jul 2013]

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.15125689).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_133640.5. 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
	MED22	NM_133640.5	MANE Select	c.592G>A	p.Glu198Lys	missense	Exon 5 of 5	NP_598395.1	Q15528-1
	MED22	NM_181491.3		c.*2599G>A		3_prime_UTR	Exon 4 of 4	NP_852468.1	Q15528-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MED22	ENST00000343730.10	TSL:1 MANE Select	c.592G>A	p.Glu198Lys	missense	Exon 5 of 5	ENSP00000342343.5	Q15528-1
	MED22	ENST00000610888.4	TSL:1	c.*2599G>A		3_prime_UTR	Exon 4 of 4	ENSP00000478773.1	Q15528-2
	MED22	ENST00000614493.4	TSL:2	c.*2599G>A		3_prime_UTR	Exon 4 of 4	ENSP00000481493.1	Q15528-2

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152192 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000585 AC: 1 AN: 170832 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000665

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000147 AC: 2 AN: 1365082 Hom.: 0 Cov.: 29 AF XY: 0.00000148 AC XY: 1 AN XY: 675126

African (AFR) AF: 0.00 AC: 0 AN: 27236

American (AMR) AF: 0.0000419 AC: 1 AN: 23844

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22552

East Asian (EAS) AF: 0.00 AC: 0 AN: 33452

South Asian (SAS) AF: 0.00 AC: 0 AN: 70254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52032

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4300

European-Non Finnish (NFE) AF: 9.30e-7 AC: 1 AN: 1075296

Other (OTH) AF: 0.00 AC: 0 AN: 56116

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152310 Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1 AN XY: 74464

African (AFR) AF: 0.00 AC: 0 AN: 41566

American (AMR) AF: 0.00 AC: 0 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68020

Other (OTH) AF: 0.00 AC: 0 AN: 2108

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.096	T
BayesDel_noAF	Benign	-0.19
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.039	T
Eigen	Benign	-0.025
Eigen_PC	Benign	0.074
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.71	T
M_CAP	Benign	0.058	D
MetaRNN	Benign	0.15	T
MetaSVM	Benign	-0.86	T
MutationAssessor	Benign	1.9	L
PhyloP100		5.8
PrimateAI	Uncertain	0.71	T
PROVEAN	Benign	-0.56	N
REVEL	Benign	0.095
Sift	Uncertain	0.012	D
Sift4G	Benign	0.071	T
Polyphen		0.34	B
Vest4		0.32
MutPred		0.22		Gain of ubiquitination at E198 (P = 9e-04)
MVP		0.53
ClinPred		0.63	D
GERP RS		4.3
Varity_R		0.12
gMVP		0.53
Mutation Taster		=86/14	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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

dbSNP: rs587668796; hg19: chr9-136208366;