3-57556446-C-T

Variant names:

• chr3-57556446-C-T
• rs2241988
• NM_177966.7:c.67C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_177966.7(PDE12):​c.67C>T​(p.Arg23Trp) variant causes a missense change. The variant allele was found at a frequency of 0.441 in 1,611,968 control chromosomes in the GnomAD database, including 160,698 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.39 (12676 hom., cov: 34)
  • Exomes 𝑓: 0.45 (148022 hom.)
• Consequence: PDE12 NM_177966.7 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.55
• Publications: 28 publications found

Genes affected

PDE12 (HGNC:25386): (phosphodiesterase 12) Enables 3'-5'-exoribonuclease activity. Involved in several processes, including RNA metabolic process; cellular response to cytokine stimulus; and regulation of mitochondrial mRNA stability. Located in mitochondrial matrix. [provided by Alliance of Genome Resources, Apr 2022]

PDE12 Gene-Disease associations (from GenCC):

• mitochondrial disease

  Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=4.518628E-4).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.546 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_177966.7. 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
	PDE12	NM_177966.7	MANE Select	c.67C>T	p.Arg23Trp	missense	Exon 1 of 3	NP_808881.3	Q6L8Q7-1
	PDE12	NM_001322176.2		c.67C>T	p.Arg23Trp	missense	Exon 1 of 3	NP_001309105.1	A0ABB0MV04
	PDE12	NM_001322177.2		c.67C>T	p.Arg23Trp	missense	Exon 1 of 2	NP_001309106.1	F6T1Q0

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PDE12	ENST00000311180.9	TSL:1 MANE Select	c.67C>T	p.Arg23Trp	missense	Exon 1 of 3	ENSP00000309142.7	Q6L8Q7-1
	PDE12	ENST00000487257.1	TSL:1	c.67C>T	p.Arg23Trp	missense	Exon 1 of 2	ENSP00000420626.1	F6T1Q0
	PDE12	ENST00000715954.1		c.67C>T	p.Arg23Trp	missense	Exon 1 of 3	ENSP00000520545.1	A0ABB0MV04

Frequencies

GnomAD3 genomes AF: 0.386 AC: 58736 AN: 152120 Hom.: 12677 Cov.: 34

Gnomad AFR AF: 0.191

Gnomad AMI AF: 0.556

Gnomad AMR AF: 0.465

Gnomad ASJ AF: 0.560

Gnomad EAS AF: 0.442

Gnomad SAS AF: 0.563

Gnomad FIN AF: 0.492

Gnomad MID AF: 0.519

Gnomad NFE AF: 0.441

Gnomad OTH AF: 0.423

GnomAD2 exomes AF: 0.455 AC: 111696 AN: 245604 AF XY: 0.466

Gnomad AFR exome AF: 0.182

Gnomad AMR exome AF: 0.442

Gnomad ASJ exome AF: 0.574

Gnomad EAS exome AF: 0.445

Gnomad FIN exome AF: 0.490

Gnomad NFE exome AF: 0.452

Gnomad OTH exome AF: 0.475

GnomAD4 exome AF: 0.446 AC: 651409 AN: 1459730 Hom.: 148022 Cov.: 82 AF XY: 0.451 AC XY: 327727 AN XY: 726116

African (AFR) AF: 0.183 AC: 6133 AN: 33470

American (AMR) AF: 0.444 AC: 19777 AN: 44502

Ashkenazi Jewish (ASJ) AF: 0.570 AC: 14855 AN: 26084

East Asian (EAS) AF: 0.475 AC: 18814 AN: 39648

South Asian (SAS) AF: 0.555 AC: 47817 AN: 86164

European-Finnish (FIN) AF: 0.486 AC: 25532 AN: 52494

Middle Eastern (MID) AF: 0.592 AC: 3399 AN: 5746

European-Non Finnish (NFE) AF: 0.439 AC: 487754 AN: 1111292

Other (OTH) AF: 0.453 AC: 27328 AN: 60330

GnomAD4 genome AF: 0.386 AC: 58742 AN: 152238 Hom.: 12676 Cov.: 34 AF XY: 0.394 AC XY: 29348 AN XY: 74426

African (AFR) AF: 0.191 AC: 7922 AN: 41566

American (AMR) AF: 0.464 AC: 7102 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.560 AC: 1942 AN: 3466

East Asian (EAS) AF: 0.442 AC: 2281 AN: 5160

South Asian (SAS) AF: 0.564 AC: 2724 AN: 4830

European-Finnish (FIN) AF: 0.492 AC: 5212 AN: 10598

Middle Eastern (MID) AF: 0.517 AC: 152 AN: 294

European-Non Finnish (NFE) AF: 0.441 AC: 30001 AN: 68000

Other (OTH) AF: 0.427 AC: 900 AN: 2110

Alfa AF: 0.429 Hom.: 11475

Bravo AF: 0.369

TwinsUK AF: 0.431 AC: 1598

ALSPAC AF: 0.426 AC: 1640

ESP6500AA AF: 0.183 AC: 803

ESP6500EA AF: 0.441 AC: 3778

ExAC AF: 0.447 AC: 54203

Asia WGS AF: 0.508 AC: 1766 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.65	T
BayesDel_noAF	Benign	-0.57
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Benign	0.024	T
Eigen	Uncertain	0.22
Eigen_PC	Uncertain	0.22
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Benign	0.72	T
MetaRNN	Benign	0.00045	T
MetaSVM	Benign	-0.89	T
MutationAssessor	Benign	1.2	L
PhyloP100		4.5
PrimateAI	Uncertain	0.63	T
PROVEAN	Benign	-0.70	N
REVEL	Benign	0.075
Sift	Benign	0.059	T
Sift4G	Uncertain	0.0060	D
Polyphen		0.99	D
Vest4		0.093
ClinPred		0.083	T
GERP RS		3.7
PromoterAI		-0.027	Neutral
Varity_R		0.19
gMVP		0.54
Mutation Taster		=96/4	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: rs2241988; hg19: chr3-57542173; COSMIC: COSV60818263;