rs748593482

Variant names:

• chr4-80202095-CCAG-C
• rs748593482
• NM_001099403.2:c.649_651delCAG

Your query was ambiguous. Multiple possible variants found:

• chr4-80202095-CCAG-C
• chr4-80202095-CCAG-CCAGCAG
• chr4-80202095-CCAG-CCAGCAGCAG
• chr4-80202095-CCAG-CCAGCAGCAGCAG

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP3

The NM_001099403.2(PRDM8):​c.649_651delCAG​(p.Gln217del) variant causes a conservative inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000913 in 1,543,848 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.000022 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000098 (0 hom.)
• Consequence: PRDM8 NM_001099403.2 conservative_inframe_deletion
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.793
• 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: Orphanet, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• 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	c.649_651delCAG	p.Gln217del	conservative_inframe_deletion	Exon 4 of 4	ENST00000415738.3	NP_001092873.1
PRDM8	NM_020226.4	c.649_651delCAG	p.Gln217del	conservative_inframe_deletion	Exon 10 of 10		NP_064611.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PRDM8	ENST00000415738.3	c.649_651delCAG	p.Gln217del	conservative_inframe_deletion	Exon 4 of 4	1	NM_001099403.2	ENSP00000406998.2
PRDM8	ENST00000339711.8	c.649_651delCAG	p.Gln217del	conservative_inframe_deletion	Exon 10 of 10	1		ENSP00000339764.4
PRDM8	ENST00000515013.5	c.649_651delCAG	p.Gln217del	conservative_inframe_deletion	Exon 10 of 10	1		ENSP00000425149.1
PRDM8	ENST00000504452.5	c.649_651delCAG	p.Gln217del	conservative_inframe_deletion	Exon 8 of 8	5		ENSP00000423985.1

Frequencies

GnomAD3 genomes AF: 0.0000222 AC: 3 AN: 135014 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000114

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000321

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000719 AC: 158 AN: 219640 AF XY: 0.000693

Gnomad AFR exome AF: 0.000518

Gnomad AMR exome AF: 0.000270

Gnomad ASJ exome AF: 0.000806

Gnomad EAS exome AF: 0.000777

Gnomad FIN exome AF: 0.000343

Gnomad NFE exome AF: 0.000979

Gnomad OTH exome AF: 0.000765

GnomAD4 exome AF: 0.0000980 AC: 138 AN: 1408730 Hom.: 0 AF XY: 0.000114 AC XY: 80 AN XY: 699960

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.000156 AC: 5 AN: 32132

American (AMR) AF: 0.000191 AC: 8 AN: 41916

Ashkenazi Jewish (ASJ) AF: 0.000241 AC: 6 AN: 24858

East Asian (EAS) AF: 0.000184 AC: 7 AN: 37968

South Asian (SAS) AF: 0.000137 AC: 11 AN: 80142

European-Finnish (FIN) AF: 0.000116 AC: 6 AN: 51524

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5596

European-Non Finnish (NFE) AF: 0.0000855 AC: 92 AN: 1076596

Other (OTH) AF: 0.0000517 AC: 3 AN: 57998

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0000222 AC: 3 AN: 135118 Hom.: 0 Cov.: 31 AF XY: 0.0000303 AC XY: 2 AN XY: 66006

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 35690

American (AMR) AF: 0.00 AC: 0 AN: 13908

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3240

East Asian (EAS) AF: 0.00 AC: 0 AN: 4350

South Asian (SAS) AF: 0.00 AC: 0 AN: 4138

European-Finnish (FIN) AF: 0.000114 AC: 1 AN: 8736

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

European-Non Finnish (NFE) AF: 0.0000322 AC: 2 AN: 62206

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

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.0168 Hom.: 0

Asia WGS AF: 0.0110 AC: 39 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.79
Mutation Taster		=96/4	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: rs748593482; hg19: chr4-81123249; COSMIC: COSV60202597; COSMIC: COSV60202597;