rs2241988

chr3-57556446-C-Gchr3-57556446-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_177966.7(PDE12):c.67C>G(p.Arg23Gly) variant causes a missense change. The variant allele was found at a frequency of 0.00000617 in 1,459,796 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R23W) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0000062 (0 hom.)
• Consequence: PDE12 NM_177966.7 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.55

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.11372286).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PDE12	NM_177966.7	c.67C>G	p.Arg23Gly	missense_variant	1/3	ENST00000311180.9
PDE12	NM_001322176.2	c.67C>G	p.Arg23Gly	missense_variant	1/3
PDE12	NM_001322177.2	c.67C>G	p.Arg23Gly	missense_variant	1/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PDE12	ENST00000311180.9	c.67C>G	p.Arg23Gly	missense_variant	1/3	1	NM_177966.7	P1
PDE12	ENST00000487257.1	c.67C>G	p.Arg23Gly	missense_variant	1/2	1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD3 exomes AF: 0.0000204 AC: 5 AN: 245604 Hom.: 0 AF XY: 0.0000374 AC XY: 5 AN XY: 133566

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000131

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000907

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000617 AC: 9 AN: 1459796 Hom.: 0 Cov.: 82 AF XY: 0.0000124 AC XY: 9 AN XY: 726160

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000812

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 34

ExAC AF: 0.0000165 AC: 2

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.062
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.59
Cadd	Benign	18
Dann	Benign	0.90
DEOGEN2	Benign	0.019	T;T
Eigen	Benign	-0.19
Eigen_PC	Benign	-0.061
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Benign	0.55	T;T
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.11	T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	1.0	P;P
PrimateAI	Uncertain	0.58	T
PROVEAN	Benign	-1.0	N;N
REVEL	Benign	0.083
Sift	Benign	0.15	T;T
Sift4G	Uncertain	0.051	T;T
Polyphen		0.0010	B;B
Vest4		0.19
MutPred		0.32		Loss of helix (P = 0.0104);Loss of helix (P = 0.0104);
MVP		0.38
ClinPred		0.49	T
GERP RS		3.7
Varity_R		0.22
gMVP		0.47

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

Publications

LitVar

Other links and lift over

dbSNP: rs2241988; hg19: chr3-57542173;