9-133345174-T-C

Variant names:

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_133640.5(MED22):c.202A>G(p.Ile68Val) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.0000353 in 1,613,800 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000038 ( 0 hom. )

Consequence

MED22
NM_133640.5 missense, splice_region

Scores

Splicing: ADA: 0.002495

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.07

Variant links:

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]

MED22 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.20082623).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MED22	NM_133640.5 link	c.202A>G	p.Ile68Val	missense_variant, splice_region_variant	Exon 3 of 5	ENST00000343730.10	NP_598395.1	Q15528-1A0A024R8C5
MED22	NM_181491.3 link	c.202A>G	p.Ile68Val	missense_variant, splice_region_variant	Exon 3 of 4		NP_852468.1	Q15528-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
MED22	ENST00000343730.10 link	c.202A>G	p.Ile68Val	missense_variant, splice_region_variant	Exon 3 of 5	1	NM_133640.5	ENSP00000342343.5	Q15528-1
MED22	ENST00000614493.4 link	c.202A>G	p.Ile68Val	missense_variant, splice_region_variant	Exon 3 of 4	2		ENSP00000481493.1	Q15528-2
MED22	ENST00000494177.6 link	c.202A>G	p.Ile68Val	missense_variant, splice_region_variant	Exon 3 of 4	4		ENSP00000420815.1	E7EN96

Frequencies

GnomAD3 genomes

AF:

0.0000132

AC:

AN:

152086

Hom.:

Cov.:

show subpopulations

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:

0.000415

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000518

AC:

AN:

251080

Hom.:

AF XY:

0.0000736

AC XY:

AN XY:

135786

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000425

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000376

AC:

AN:

1461596

Hom.:

Cov.:

AF XY:

0.0000468

AC XY:

AN XY:

727128

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000614

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152204

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74424

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000416

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

ExAC

AF:

0.0000659

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Dec 08, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.202A>G (p.I68V) alteration is located in exon 3 (coding exon 2) of the MED22 gene. This alteration results from a A to G substitution at nucleotide position 202, causing the isoleucine (I) at amino acid position 68 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.17

BayesDel_addAF

Benign

-0.20

BayesDel_noAF

Benign

-0.20

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.067

T;T;.;.;T;.;.

Eigen

Benign

0.0075

Eigen_PC

Benign

0.095

FATHMM_MKL

Uncertain

0.92

LIST_S2

Uncertain

0.96

.;D;.;D;D;D;D

M_CAP

Benign

0.012

MetaRNN

Benign

0.20

T;T;T;T;T;T;T

MetaSVM

Benign

-0.81

MutationAssessor

Benign

1.6

L;L;L;L;.;.;.

PrimateAI

Pathogenic

0.83

PROVEAN

Benign

-0.41

.;N;.;.;N;N;N

REVEL

Benign

0.18

Sift

Benign

0.12

.;T;.;.;T;T;T

Sift4G

Benign

0.11

T;T;T;T;.;T;T

Polyphen

0.62

P;P;B;B;.;.;.

Vest4

0.30

MutPred

0.58

Gain of MoRF binding (P = 0.1202);Gain of MoRF binding (P = 0.1202);Gain of MoRF binding (P = 0.1202);Gain of MoRF binding (P = 0.1202);Gain of MoRF binding (P = 0.1202);Gain of MoRF binding (P = 0.1202);Gain of MoRF binding (P = 0.1202);

MVP

0.56

ClinPred

0.11

GERP RS

4.7

Varity_R

0.21

gMVP

0.77

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.0025

dbscSNV1_RF

Benign

0.13

SpliceAI score (max)

0.040

Details are displayed if max score is > 0.2

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over