22-20564628-CCAGCAGCAGCAGCAGCAG-CCAGCAGCAGCAGCAG

Variant names:

• chr22-20564628-CCAG-C
• rs374794651
• NM_001003891.3:c.654_656delGCA

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP3 BS1 BS2

The NM_001003891.3(MED15):​c.654_656delGCA​(p.Gln218del) variant causes a disruptive inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00313 in 1,535,852 control chromosomes in the GnomAD database, including 44 homozygotes. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0099 (28 hom., cov: 33)
  • Exomes 𝑓: 0.0024 (16 hom.)
• Consequence: MED15 NM_001003891.3 disruptive_inframe_deletion
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.48
• Publications: 6 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
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00988 (1492/151034) while in subpopulation AFR AF = 0.0327 (1343/41106). AF 95% confidence interval is 0.0312. There are 28 homozygotes in GnomAd4. There are 691 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1492 AD gene.

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.654_656delGCA	p.Gln218del	disruptive_inframe_deletion	Exon 6 of 18	NP_001003891.1	Q96RN5-1
	MED15	NM_015889.5		c.654_656delGCA	p.Gln218del	disruptive_inframe_deletion	Exon 6 of 17	NP_056973.2
	MED15	NM_001293234.2		c.654_656delGCA	p.Gln218del	disruptive_inframe_deletion	Exon 6 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.654_656delGCA	p.Gln218del	disruptive_inframe_deletion	Exon 6 of 18	ENSP00000263205.7	Q96RN5-1
	MED15	ENST00000292733.11	TSL:1	c.654_656delGCA	p.Gln218del	disruptive_inframe_deletion	Exon 6 of 17	ENSP00000292733.7	Q96RN5-2
	MED15	ENST00000406969.5	TSL:1	c.576_578delGCA	p.Gln192del	disruptive_inframe_deletion	Exon 6 of 17	ENSP00000384344.1	G3V1P5

Frequencies

GnomAD3 genomes AF: 0.00988 AC: 1491 AN: 150916 Hom.: 28 Cov.: 33

Gnomad AFR AF: 0.0327

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00376

Gnomad ASJ AF: 0.000578

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00523

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00637

Gnomad NFE AF: 0.000636

Gnomad OTH AF: 0.00916

GnomAD2 exomes AF: 0.00640 AC: 1325 AN: 207078 AF XY: 0.00595

Gnomad AFR exome AF: 0.0374

Gnomad AMR exome AF: 0.00438

Gnomad ASJ exome AF: 0.00253

Gnomad EAS exome AF: 0.00183

Gnomad FIN exome AF: 0.00146

Gnomad NFE exome AF: 0.00422

Gnomad OTH exome AF: 0.00290

GnomAD4 exome AF: 0.00240 AC: 3320 AN: 1384818 Hom.: 16 AF XY: 0.00240 AC XY: 1654 AN XY: 687760

African (AFR) AF: 0.0337 AC: 1070 AN: 31736

American (AMR) AF: 0.00376 AC: 159 AN: 42252

Ashkenazi Jewish (ASJ) AF: 0.00124 AC: 31 AN: 24970

East Asian (EAS) AF: 0.000317 AC: 12 AN: 37868

South Asian (SAS) AF: 0.00664 AC: 528 AN: 79532

European-Finnish (FIN) AF: 0.000632 AC: 32 AN: 50600

Middle Eastern (MID) AF: 0.00397 AC: 22 AN: 5542

European-Non Finnish (NFE) AF: 0.00118 AC: 1249 AN: 1055206

Other (OTH) AF: 0.00380 AC: 217 AN: 57112

GnomAD4 genome AF: 0.00988 AC: 1492 AN: 151034 Hom.: 28 Cov.: 33 AF XY: 0.00936 AC XY: 691 AN XY: 73806

African (AFR) AF: 0.0327 AC: 1343 AN: 41106

American (AMR) AF: 0.00375 AC: 57 AN: 15182

Ashkenazi Jewish (ASJ) AF: 0.000578 AC: 2 AN: 3460

East Asian (EAS) AF: 0.000194 AC: 1 AN: 5160

South Asian (SAS) AF: 0.00523 AC: 25 AN: 4780

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10416

Middle Eastern (MID) AF: 0.00685 AC: 2 AN: 292

European-Non Finnish (NFE) AF: 0.000636 AC: 43 AN: 67632

Other (OTH) AF: 0.00906 AC: 19 AN: 2096

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0111

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		2.5
Mutation Taster		=80/20	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: rs374794651; hg19: chr22-20918915; COSMIC: COSV53026445; COSMIC: COSV53026445;