rs12780

Variant names:

• chr4-80203442-G-C
• rs12780
• NM_001099403.2:c.1980G>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001099403.2(PRDM8):​c.1980G>C​(p.Arg660Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.28 in 1,612,362 control chromosomes in the GnomAD database, including 67,937 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.27 (6195 hom., cov: 31)
  • Exomes 𝑓: 0.28 (61742 hom.)
• Consequence: PRDM8 NM_001099403.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.583
• Publications: 19 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: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.66).
• BP6: Variant 4-80203442-G-C is Benign according to our data. Variant chr4-80203442-G-C is described in ClinVar as Benign. ClinVar VariationId is 1170071.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.583 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.6 is higher than 0.05.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PRDM8	NM_001099403.2	MANE Select	c.1980G>C	p.Arg660Arg	synonymous	Exon 4 of 4	NP_001092873.1
	PRDM8	NM_020226.4		c.1980G>C	p.Arg660Arg	synonymous	Exon 10 of 10	NP_064611.3

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PRDM8	ENST00000415738.3	TSL:1 MANE Select	c.1980G>C	p.Arg660Arg	synonymous	Exon 4 of 4	ENSP00000406998.2
	PRDM8	ENST00000339711.8	TSL:1	c.1980G>C	p.Arg660Arg	synonymous	Exon 10 of 10	ENSP00000339764.4
	PRDM8	ENST00000504452.5	TSL:5	c.1980G>C	p.Arg660Arg	synonymous	Exon 8 of 8	ENSP00000423985.1

Frequencies

GnomAD3 genomes AF: 0.273 AC: 41388 AN: 151836 Hom.: 6188 Cov.: 31

Gnomad AFR AF: 0.191

Gnomad AMI AF: 0.277

Gnomad AMR AF: 0.331

Gnomad ASJ AF: 0.276

Gnomad EAS AF: 0.617

Gnomad SAS AF: 0.384

Gnomad FIN AF: 0.357

Gnomad MID AF: 0.237

Gnomad NFE AF: 0.262

Gnomad OTH AF: 0.284

GnomAD2 exomes AF: 0.321 AC: 78956 AN: 245986 AF XY: 0.320

Gnomad AFR exome AF: 0.185

Gnomad AMR exome AF: 0.366

Gnomad ASJ exome AF: 0.262

Gnomad EAS exome AF: 0.632

Gnomad FIN exome AF: 0.352

Gnomad NFE exome AF: 0.263

Gnomad OTH exome AF: 0.306

GnomAD4 exome AF: 0.281 AC: 410148 AN: 1460412 Hom.: 61742 Cov.: 45 AF XY: 0.283 AC XY: 205600 AN XY: 726324

African (AFR) AF: 0.190 AC: 6355 AN: 33464

American (AMR) AF: 0.365 AC: 16214 AN: 44462

Ashkenazi Jewish (ASJ) AF: 0.269 AC: 7027 AN: 26104

East Asian (EAS) AF: 0.618 AC: 24504 AN: 39648

South Asian (SAS) AF: 0.368 AC: 31626 AN: 85964

European-Finnish (FIN) AF: 0.349 AC: 18619 AN: 53300

Middle Eastern (MID) AF: 0.281 AC: 1618 AN: 5764

European-Non Finnish (NFE) AF: 0.258 AC: 286596 AN: 1111352

Other (OTH) AF: 0.291 AC: 17589 AN: 60354

GnomAD4 genome AF: 0.273 AC: 41416 AN: 151950 Hom.: 6195 Cov.: 31 AF XY: 0.284 AC XY: 21079 AN XY: 74230

African (AFR) AF: 0.191 AC: 7908 AN: 41442

American (AMR) AF: 0.332 AC: 5062 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.276 AC: 956 AN: 3470

East Asian (EAS) AF: 0.618 AC: 3173 AN: 5138

South Asian (SAS) AF: 0.383 AC: 1845 AN: 4820

European-Finnish (FIN) AF: 0.357 AC: 3770 AN: 10554

Middle Eastern (MID) AF: 0.228 AC: 67 AN: 294

European-Non Finnish (NFE) AF: 0.262 AC: 17786 AN: 67940

Other (OTH) AF: 0.283 AC: 597 AN: 2112

Alfa AF: 0.259 Hom.: 1682

Bravo AF: 0.266

Asia WGS AF: 0.487 AC: 1688 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	Early-onset Lafora body disease (2)
-	-	2	not provided (2)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.66
CADD	Benign	7.5
DANN	Benign	0.79
PhyloP100		-0.58
Mutation Taster		=100/0	polymorphism (auto)

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: rs12780; hg19: chr4-81124596; COSMIC: COSV60202903; COSMIC: COSV60202903;