Genetic Variant NM_018945.4:c.764G>C (chr6-136173849-G-C) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_018945.4(PDE7B):c.764G>C(p.Arg255Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,460,604 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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. R255Q) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

PDE7B
NM_018945.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 9.92

Publications

1 publications found

Variant links:

Genes affected

PDE7B (HGNC:8792): (phosphodiesterase 7B) The 3',5'-cyclic nucleotides cAMP and cGMP function as second messengers in a wide variety of signal transduction pathways. 3',5'-cyclic nucleotide phosphodiesterases (PDEs) catalyze the hydrolysis of cAMP and cGMP to the corresponding 5'-monophosphates and provide a mechanism to downregulate cAMP and cGMP signaling. This gene encodes a cAMP-specific phosphodiesterase, a member of the cyclic nucleotide phosphodiesterase family.[provided by RefSeq, Apr 2009]

PDE7B links:

PDE7B-AS1 (HGNC:56334): (PDE7B antisense RNA 1)

PDE7B-AS1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.889

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PDE7B	NM_018945.4 link	c.764G>C	p.Arg255Pro	missense_variant	Exon 9 of 13	ENST00000308191.11	NP_061818.1	Q9NP56

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PDE7B	ENST00000308191.11 link	c.764G>C	p.Arg255Pro	missense_variant	Exon 9 of 13	1	NM_018945.4	ENSP00000310661.6		Q9NP56

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000399

AC:

AN:

250836

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.0000993

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1460604

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

726718

show subpopulations

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

African (AFR)

AF:

0.00

AC:

AN:

33418

American (AMR)

AF:

0.00

AC:

AN:

44632

Ashkenazi Jewish (ASJ)

AF:

0.0000383

AC:

AN:

26112

East Asian (EAS)

AF:

0.00

AC:

AN:

39690

South Asian (SAS)

AF:

0.00

AC:

AN:

86250

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53384

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5760

European-Non Finnish (NFE)

AF:

9.00e-7

AC:

AN:

1111024

Other (OTH)

AF:

0.00

AC:

AN:

60334

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.300

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000244

Hom.:

EpiCase

AF:

0.0000546

EpiControl

AF:

0.00

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

BayesDel_addAF

Pathogenic

0.35

BayesDel_noAF

Pathogenic

0.26

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.69

D;D

Eigen

Pathogenic

0.95

Eigen_PC

Pathogenic

0.92

FATHMM_MKL

Uncertain

0.97

LIST_S2

Uncertain

0.96

D;D

M_CAP

Uncertain

0.090

MetaRNN

Pathogenic

0.89

D;D

MetaSVM

Uncertain

0.30

MutationAssessor

Uncertain

2.4

M;.

PhyloP100

9.9

PrimateAI

Pathogenic

0.80

PROVEAN

Uncertain

-3.7

D;.

REVEL

Pathogenic

0.78

Sift

Benign

0.034

D;.

Sift4G

Benign

0.12

T;T

Polyphen

1.0

D;D

Vest4

0.87

MutPred

0.70

Loss of MoRF binding (P = 0.0021);.;

MVP

0.65

MPC

1.3

ClinPred

0.98

GERP RS

5.5

Varity_R

0.96

gMVP

0.88

Mutation Taster

=17/83

disease causing

(source)

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

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NM_018945.4:c.764G>C

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over