22-20564628-CCAGCAGCAGCAGCAGCAG-CCAGCAGCAGCAGCAGCAGCAG

Variant names:

• chr22-20564628-C-CCAG
• rs374794651
• NM_001003891.3:c.654_656dupGCA

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP3 BP6_Moderate BS2

The NM_001003891.3(MED15):​c.654_656dupGCA​(p.Gln218dup) variant causes a disruptive inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00528 in 1,606,648 control chromosomes in the GnomAD database, including 28 homozygotes. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0049 (3 hom., cov: 33)
  • Exomes 𝑓: 0.0053 (25 hom.)
• Consequence: MED15 NM_001003891.3 disruptive_inframe_insertion
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• 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 -7 ACMG points.

• BP3: Nonframeshift variant in repetitive region in NM_001003891.3
• BP6: Variant 22-20564628-C-CCAG is Benign according to our data. Variant chr22-20564628-C-CCAG is described in ClinVar as Likely_benign. ClinVar VariationId is 2652902.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAd4 at 735 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_656dupGCA	p.Gln218dup	disruptive_inframe_insertion	Exon 6 of 18	NP_001003891.1	Q96RN5-1
	MED15	NM_015889.5		c.654_656dupGCA	p.Gln218dup	disruptive_inframe_insertion	Exon 6 of 17	NP_056973.2
	MED15	NM_001293234.2		c.654_656dupGCA	p.Gln218dup	disruptive_inframe_insertion	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_656dupGCA	p.Gln218dup	disruptive_inframe_insertion	Exon 6 of 18	ENSP00000263205.7	Q96RN5-1
	MED15	ENST00000292733.11	TSL:1	c.654_656dupGCA	p.Gln218dup	disruptive_inframe_insertion	Exon 6 of 17	ENSP00000292733.7	Q96RN5-2
	MED15	ENST00000406969.5	TSL:1	c.576_578dupGCA	p.Gln192dup	disruptive_inframe_insertion	Exon 6 of 17	ENSP00000384344.1	G3V1P5

Frequencies

GnomAD3 genomes AF: 0.00487 AC: 735 AN: 150976 Hom.: 3 Cov.: 33

Gnomad AFR AF: 0.00329

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00851

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.00155

Gnomad SAS AF: 0.00272

Gnomad FIN AF: 0.00230

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00590

Gnomad OTH AF: 0.00964

GnomAD2 exomes AF: 0.00526 AC: 1089 AN: 207078 AF XY: 0.00539

Gnomad AFR exome AF: 0.00260

Gnomad AMR exome AF: 0.00642

Gnomad ASJ exome AF: 0.00242

Gnomad EAS exome AF: 0.000950

Gnomad FIN exome AF: 0.00340

Gnomad NFE exome AF: 0.00687

Gnomad OTH exome AF: 0.00541

GnomAD4 exome AF: 0.00533 AC: 7751 AN: 1455554 Hom.: 25 Cov.: 35 AF XY: 0.00540 AC XY: 3912 AN XY: 724056

African (AFR) AF: 0.00283 AC: 94 AN: 33234

American (AMR) AF: 0.00553 AC: 246 AN: 44508

Ashkenazi Jewish (ASJ) AF: 0.00188 AC: 49 AN: 26086

East Asian (EAS) AF: 0.000834 AC: 33 AN: 39574

South Asian (SAS) AF: 0.00359 AC: 308 AN: 85782

European-Finnish (FIN) AF: 0.00300 AC: 159 AN: 53048

Middle Eastern (MID) AF: 0.00521 AC: 30 AN: 5754

European-Non Finnish (NFE) AF: 0.00587 AC: 6506 AN: 1107468

Other (OTH) AF: 0.00542 AC: 326 AN: 60100

GnomAD4 genome AF: 0.00486 AC: 735 AN: 151094 Hom.: 3 Cov.: 33 AF XY: 0.00471 AC XY: 348 AN XY: 73846

African (AFR) AF: 0.00328 AC: 135 AN: 41116

American (AMR) AF: 0.00843 AC: 128 AN: 15186

Ashkenazi Jewish (ASJ) AF: 0.00173 AC: 6 AN: 3462

East Asian (EAS) AF: 0.00155 AC: 8 AN: 5160

South Asian (SAS) AF: 0.00272 AC: 13 AN: 4780

European-Finnish (FIN) AF: 0.00230 AC: 24 AN: 10432

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

European-Non Finnish (NFE) AF: 0.00591 AC: 400 AN: 67660

Other (OTH) AF: 0.00954 AC: 20 AN: 2096

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00499

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		2.5
Mutation Taster		=76/24	polymorphism

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: COSV53027526; COSMIC: COSV53027526;