4-80202095-CCAG-CCAGCAG

Variant names:

• chr4-80202095-C-CCAG
• rs748593482
• NM_001099403.2:c.649_651dupCAG

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BP3

The NM_001099403.2(PRDM8):​c.649_651dupCAG​(p.Gln217dup) variant causes a conservative inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000244 in 1,591,500 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. E218E) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00041 (1 hom., cov: 31)
  • Exomes 𝑓: 0.00023 (0 hom.)
• Consequence: PRDM8 NM_001099403.2 conservative_inframe_insertion
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.336
• Publications: 2 publications found

Genes affected

PRDM8 (HGNC:13993): (PR/SET domain 8) This gene encodes a protein that belongs to a conserved family of histone methyltransferases that predominantly act as negative regulators of transcription. The encoded protein contains an N-terminal Su(var)3-9, Enhancer-of-zeste, and Trithorax (SET) domain and a double zinc-finger domain. Knockout of this gene in mouse results in mistargeting by neurons of the dorsal telencephalon, abnormal itch-like behavior, and impaired differentiation of rod bipolar cells. In humans, the protein has been shown to interact with the phosphatase laforin and the ubiquitin ligase malin, which regulate glycogen construction in the cytoplasm. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Feb 2016]

PRDM8 Gene-Disease associations (from GenCC):

• early-onset Lafora body disease

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -1 ACMG points.

• BP3: Nonframeshift variant in repetitive region in NM_001099403.2

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001099403.2. 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
	PRDM8	NM_001099403.2	MANE Select	c.649_651dupCAG	p.Gln217dup	conservative_inframe_insertion	Exon 4 of 4	NP_001092873.1	Q9NQV8-1
	PRDM8	NM_020226.4		c.649_651dupCAG	p.Gln217dup	conservative_inframe_insertion	Exon 10 of 10	NP_064611.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PRDM8	ENST00000415738.3	TSL:1 MANE Select	c.649_651dupCAG	p.Gln217dup	conservative_inframe_insertion	Exon 4 of 4	ENSP00000406998.2	Q9NQV8-1
	PRDM8	ENST00000339711.8	TSL:1	c.649_651dupCAG	p.Gln217dup	conservative_inframe_insertion	Exon 10 of 10	ENSP00000339764.4	Q9NQV8-1
	PRDM8	ENST00000515013.5	TSL:1	c.649_651dupCAG	p.Gln217dup	conservative_inframe_insertion	Exon 10 of 10	ENSP00000425149.1	E9PEH0

Frequencies

GnomAD3 genomes AF: 0.000407 AC: 55 AN: 135104 Hom.: 1 Cov.: 31

Gnomad AFR AF: 0.000140

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000229

Gnomad SAS AF: 0.000483

Gnomad FIN AF: 0.000912

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000627

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000351 AC: 77 AN: 219640 AF XY: 0.000317

Gnomad AFR exome AF: 0.0000741

Gnomad AMR exome AF: 0.000507

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000882

Gnomad NFE exome AF: 0.000360

Gnomad OTH exome AF: 0.000382

GnomAD4 exome AF: 0.000229 AC: 334 AN: 1456292 Hom.: 0 Cov.: 39 AF XY: 0.000244 AC XY: 177 AN XY: 724444

African (AFR) AF: 0.000120 AC: 4 AN: 33320

American (AMR) AF: 0.000385 AC: 17 AN: 44166

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25938

East Asian (EAS) AF: 0.00 AC: 0 AN: 39470

South Asian (SAS) AF: 0.000501 AC: 43 AN: 85768

European-Finnish (FIN) AF: 0.000641 AC: 34 AN: 53020

Middle Eastern (MID) AF: 0.000174 AC: 1 AN: 5748

European-Non Finnish (NFE) AF: 0.000198 AC: 220 AN: 1108766

Other (OTH) AF: 0.000250 AC: 15 AN: 60096

GnomAD4 genome AF: 0.000407 AC: 55 AN: 135208 Hom.: 1 Cov.: 31 AF XY: 0.000303 AC XY: 20 AN XY: 66056

African (AFR) AF: 0.000140 AC: 5 AN: 35704

American (AMR) AF: 0.00 AC: 0 AN: 13910

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3242

East Asian (EAS) AF: 0.000230 AC: 1 AN: 4350

South Asian (SAS) AF: 0.000483 AC: 2 AN: 4138

European-Finnish (FIN) AF: 0.000912 AC: 8 AN: 8776

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 178

European-Non Finnish (NFE) AF: 0.000627 AC: 39 AN: 62238

Other (OTH) AF: 0.00 AC: 0 AN: 1866

Alfa AF: 0.00107 Hom.: 0

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Early-onset Lafora body disease (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.34
Mutation Taster		=90/10	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs748593482; hg19: chr4-81123249;