22-20564628-CCAGCAGCAGCAGCAGCAG-CCAGCAGCAGCAG

Variant names:

• chr22-20564628-CCAGCAG-C
• rs374794651
• NM_001003891.3:c.651_656delGCAGCA

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP3 BS2

The NM_001003891.3(MED15):​c.651_656delGCAGCA​(p.Gln217_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 0.00121 in 1,606,622 control chromosomes in the GnomAD database, including 4 homozygotes. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0013 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0012 (4 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: Likely_benign. The variant received -5 ACMG points.

• BP3: Nonframeshift variant in repetitive region in NM_001003891.3
• BS2: High AC in GnomAd4 at 202 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.651_656delGCAGCA	p.Gln217_Gln218del	disruptive_inframe_deletion	Exon 6 of 18	NP_001003891.1	Q96RN5-1
	MED15	NM_015889.5		c.651_656delGCAGCA	p.Gln217_Gln218del	disruptive_inframe_deletion	Exon 6 of 17	NP_056973.2
	MED15	NM_001293234.2		c.651_656delGCAGCA	p.Gln217_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.651_656delGCAGCA	p.Gln217_Gln218del	disruptive_inframe_deletion	Exon 6 of 18	ENSP00000263205.7	Q96RN5-1
	MED15	ENST00000292733.11	TSL:1	c.651_656delGCAGCA	p.Gln217_Gln218del	disruptive_inframe_deletion	Exon 6 of 17	ENSP00000292733.7	Q96RN5-2
	MED15	ENST00000406969.5	TSL:1	c.573_578delGCAGCA	p.Gln191_Gln192del	disruptive_inframe_deletion	Exon 6 of 17	ENSP00000384344.1	G3V1P5

Frequencies

GnomAD3 genomes AF: 0.00134 AC: 202 AN: 150976 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000390

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000593

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000209

Gnomad FIN AF: 0.00153

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00222

Gnomad OTH AF: 0.00241

GnomAD2 exomes AF: 0.00151 AC: 313 AN: 207078 AF XY: 0.00147

Gnomad AFR exome AF: 0.000306

Gnomad AMR exome AF: 0.000451

Gnomad ASJ exome AF: 0.00209

Gnomad EAS exome AF: 0.000136

Gnomad FIN exome AF: 0.00227

Gnomad NFE exome AF: 0.00229

Gnomad OTH exome AF: 0.00135

GnomAD4 exome AF: 0.00120 AC: 1742 AN: 1455528 Hom.: 4 AF XY: 0.00118 AC XY: 857 AN XY: 724048

African (AFR) AF: 0.000301 AC: 10 AN: 33234

American (AMR) AF: 0.000427 AC: 19 AN: 44502

Ashkenazi Jewish (ASJ) AF: 0.00173 AC: 45 AN: 26086

East Asian (EAS) AF: 0.000101 AC: 4 AN: 39574

South Asian (SAS) AF: 0.000583 AC: 50 AN: 85778

European-Finnish (FIN) AF: 0.00183 AC: 97 AN: 53046

Middle Eastern (MID) AF: 0.000348 AC: 2 AN: 5754

European-Non Finnish (NFE) AF: 0.00130 AC: 1441 AN: 1107460

Other (OTH) AF: 0.00123 AC: 74 AN: 60094

GnomAD4 genome AF: 0.00134 AC: 202 AN: 151094 Hom.: 0 Cov.: 33 AF XY: 0.00131 AC XY: 97 AN XY: 73844

African (AFR) AF: 0.000389 AC: 16 AN: 41116

American (AMR) AF: 0.000593 AC: 9 AN: 15186

Ashkenazi Jewish (ASJ) AF: 0.00144 AC: 5 AN: 3462

East Asian (EAS) AF: 0.00 AC: 0 AN: 5160

South Asian (SAS) AF: 0.000209 AC: 1 AN: 4780

European-Finnish (FIN) AF: 0.00153 AC: 16 AN: 10432

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.00222 AC: 150 AN: 67660

Other (OTH) AF: 0.00239 AC: 5 AN: 2096

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00116

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		2.5
Mutation Taster		=114/86	disease causing (fs/PTC)

Splicing

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: COSV53034107; COSMIC: COSV53034107;