22-20566526-A-ACAG

Variant names:

• chr22-20566526-A-ACAG
• NM_001003891.3:c.784_786dupCAG

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP3 BA1

The NM_001003891.3(MED15):​c.784_786dupCAG​(p.Gln262dup) variant causes a conservative inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.168 in 1,600,742 control chromosomes in the GnomAD database, including 4,968 homozygotes. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.16 (1970 hom., cov: 27)
  • Exomes 𝑓: 0.17 (2998 hom.)
• Consequence: MED15 NM_001003891.3 conservative_inframe_insertion
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.721
• Publications: 0 publications found

Genes affected

MED15 (HGNC:14248): (mediator complex subunit 15) The protein encoded by this gene is a subunit of the multiprotein complexes PC2 and ARC/DRIP and may function as a transcriptional coactivator in RNA polymerase II transcription. This gene contains stretches of trinucleotide repeats and is located in the chromosome 22 region which is deleted in DiGeorge syndrome. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jun 2014]

ENSG00000307622 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -9 ACMG points.

• BP3: Nonframeshift variant in repetitive region in NM_001003891.3
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.188 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001003891.3. 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
	MED15	NM_001003891.3	MANE Select	c.784_786dupCAG	p.Gln262dup	conservative_inframe_insertion	Exon 7 of 18	NP_001003891.1	Q96RN5-1
	MED15	NM_015889.5		c.784_786dupCAG	p.Gln262dup	conservative_inframe_insertion	Exon 7 of 17	NP_056973.2
	MED15	NM_001293234.2		c.784_786dupCAG	p.Gln262dup	conservative_inframe_insertion	Exon 7 of 17	NP_001280163.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MED15	ENST00000263205.11	TSL:1 MANE Select	c.784_786dupCAG	p.Gln262dup	conservative_inframe_insertion	Exon 7 of 18	ENSP00000263205.7	Q96RN5-1
	MED15	ENST00000292733.11	TSL:1	c.784_786dupCAG	p.Gln262dup	conservative_inframe_insertion	Exon 7 of 17	ENSP00000292733.7	Q96RN5-2
	MED15	ENST00000406969.5	TSL:1	c.706_708dupCAG	p.Gln236dup	conservative_inframe_insertion	Exon 7 of 17	ENSP00000384344.1	G3V1P5

Frequencies

GnomAD3 genomes AF: 0.160 AC: 24004 AN: 150492 Hom.: 1968 Cov.: 27

Gnomad AFR AF: 0.117

Gnomad AMI AF: 0.210

Gnomad AMR AF: 0.118

Gnomad ASJ AF: 0.0992

Gnomad EAS AF: 0.134

Gnomad SAS AF: 0.198

Gnomad FIN AF: 0.202

Gnomad MID AF: 0.0669

Gnomad NFE AF: 0.191

Gnomad OTH AF: 0.152

GnomAD2 exomes AF: 0.241 AC: 35290 AN: 146270 AF XY: 0.249

Gnomad AFR exome AF: 0.165

Gnomad AMR exome AF: 0.212

Gnomad ASJ exome AF: 0.180

Gnomad EAS exome AF: 0.225

Gnomad FIN exome AF: 0.236

Gnomad NFE exome AF: 0.252

Gnomad OTH exome AF: 0.242

GnomAD4 exome AF: 0.169 AC: 245572 AN: 1450138 Hom.: 2998 Cov.: 26 AF XY: 0.170 AC XY: 122502 AN XY: 721552

African (AFR) AF: 0.104 AC: 3453 AN: 33362

American (AMR) AF: 0.101 AC: 4487 AN: 44528

Ashkenazi Jewish (ASJ) AF: 0.0950 AC: 2473 AN: 26038

East Asian (EAS) AF: 0.118 AC: 4673 AN: 39536

South Asian (SAS) AF: 0.181 AC: 15581 AN: 85860

European-Finnish (FIN) AF: 0.176 AC: 9015 AN: 51288

Middle Eastern (MID) AF: 0.0671 AC: 382 AN: 5690

European-Non Finnish (NFE) AF: 0.177 AC: 195838 AN: 1103896

Other (OTH) AF: 0.161 AC: 9670 AN: 59940

GnomAD4 genome AF: 0.159 AC: 24013 AN: 150604 Hom.: 1970 Cov.: 27 AF XY: 0.160 AC XY: 11733 AN XY: 73504

African (AFR) AF: 0.117 AC: 4814 AN: 41200

American (AMR) AF: 0.118 AC: 1782 AN: 15134

Ashkenazi Jewish (ASJ) AF: 0.0992 AC: 342 AN: 3448

East Asian (EAS) AF: 0.134 AC: 687 AN: 5114

South Asian (SAS) AF: 0.199 AC: 944 AN: 4750

European-Finnish (FIN) AF: 0.202 AC: 2065 AN: 10240

Middle Eastern (MID) AF: 0.0724 AC: 21 AN: 290

European-Non Finnish (NFE) AF: 0.191 AC: 12854 AN: 67456

Other (OTH) AF: 0.152 AC: 315 AN: 2074

Alfa AF: 0.0958 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.72
Mutation Taster		=66/34	polymorphism (auto)

Splicing

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

Other links and lift over

hg19: chr22-20920813; COSMIC: COSV53026653; COSMIC: COSV53026653;