4-80202095-C-CCAG

Variant names:

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

Scores

Not classified

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.336

Publications

2 publications found

Variant links:

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: Orphanet, Labcorp Genetics (formerly Invitae)

PRDM8 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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

BP3

Nonframeshift variant in repetitive region in NM_001099403.2

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PRDM8	NM_001099403.2 link	c.649_651dupCAG	p.Gln217dup	conservative_inframe_insertion	Exon 4 of 4	ENST00000415738.3	NP_001092873.1	Q9NQV8-1A0A024RDC4Q05CA1
PRDM8	NM_020226.4 link	c.649_651dupCAG	p.Gln217dup	conservative_inframe_insertion	Exon 10 of 10		NP_064611.3	Q9NQV8-1A0A024RDC4Q05CA1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
PRDM8	ENST00000415738.3 link	c.649_651dupCAG	p.Gln217dup	conservative_inframe_insertion	Exon 4 of 4	1	NM_001099403.2	ENSP00000406998.2	Q9NQV8-1
PRDM8	ENST00000339711.8 link	c.649_651dupCAG	p.Gln217dup	conservative_inframe_insertion	Exon 10 of 10	1		ENSP00000339764.4	Q9NQV8-1
PRDM8	ENST00000515013.5 link	c.649_651dupCAG	p.Gln217dup	conservative_inframe_insertion	Exon 10 of 10	1		ENSP00000425149.1	E9PEH0
PRDM8	ENST00000504452.5 link	c.649_651dupCAG	p.Gln217dup	conservative_inframe_insertion	Exon 8 of 8	5		ENSP00000423985.1	Q9NQV8-1

Frequencies

GnomAD3 genomes

AF:

0.000407

AC:

AN:

135104

Hom.:

Cov.:

show subpopulations

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:

AN:

219640

AF XY:

0.000317

show subpopulations

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.:

Cov.:

AF XY:

0.000244

AC XY:

177

AN XY:

724444

show subpopulations

African (AFR)

AF:

0.000120

AC:

AN:

33320

American (AMR)

AF:

0.000385

AC:

AN:

44166

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25938

East Asian (EAS)

AF:

0.00

AC:

AN:

39470

South Asian (SAS)

AF:

0.000501

AC:

AN:

85768

European-Finnish (FIN)

AF:

0.000641

AC:

AN:

53020

Middle Eastern (MID)

AF:

0.000174

AC:

AN:

5748

European-Non Finnish (NFE)

AF:

0.000198

AC:

220

AN:

1108766

Other (OTH)

AF:

0.000250

AC:

AN:

60096

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.468

Heterozygous variant carriers

115

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000407

AC:

AN:

135208

Hom.:

Cov.:

AF XY:

0.000303

AC XY:

AN XY:

66056

show subpopulations

African (AFR)

AF:

0.000140

AC:

AN:

35704

American (AMR)

AF:

0.00

AC:

AN:

13910

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3242

East Asian (EAS)

AF:

0.000230

AC:

AN:

4350

South Asian (SAS)

AF:

0.000483

AC:

AN:

4138

European-Finnish (FIN)

AF:

0.000912

AC:

AN:

8776

Middle Eastern (MID)

AF:

0.00

AC:

AN:

178

European-Non Finnish (NFE)

AF:

0.000627

AC:

AN:

62238

Other (OTH)

AF:

0.00

AC:

AN:

1866

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00107

Hom.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Early-onset Lafora body disease

Uncertain:1

Oct 25, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant, c.649_651dup, results in the insertion of 1 amino acid(s) of the PRDM8 protein (p.Gln217dup), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs769916001, gnomAD 0.08%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with PRDM8-related conditions. ClinVar contains an entry for this variant (Variation ID: 475682). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

-0.34

Mutation Taster

=90/10

polymorphism

(source)

Splicing

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over