9-133341516-C-A

Variant names:

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

Variant summary

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

The NM_133640.5(MED22):​c.592G>T​(p.Glu198*) variant causes a stop gained change. The variant allele was found at a frequency of 0.000000733 in 1,365,082 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.3e-7 (0 hom.)
• Consequence: MED22 NM_133640.5 stop_gained
• Clinical Significance: Not reported in ClinVar
• 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 2 ACMG points.

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

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>T	p.Glu198*	stop_gained	Exon 5 of 5	NP_598395.1	Q15528-1
	MED22	NM_181491.3		c.*2599G>T		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>T	p.Glu198*	stop_gained	Exon 5 of 5	ENSP00000342343.5	Q15528-1
	MED22	ENST00000610888.4	TSL:1	c.*2599G>T		3_prime_UTR	Exon 4 of 4	ENSP00000478773.1	Q15528-2
	MED22	ENST00000614493.4	TSL:2	c.*2599G>T		3_prime_UTR	Exon 4 of 4	ENSP00000481493.1	Q15528-2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.33e-7 AC: 1 AN: 1365082 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 675126

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

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

American (AMR) AF: 0.00 AC: 0 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

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.60	D
BayesDel_noAF	Pathogenic	0.62
CADD	Pathogenic	38
DANN	Uncertain	1.0
Eigen	Pathogenic	0.93
Eigen_PC	Pathogenic	0.71
FATHMM_MKL	Pathogenic	0.99	D
PhyloP100		5.8
Vest4		0.22
GERP RS		4.3
Mutation Taster		=79/121	disease causing

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;