6-136191834-C-G

Position:

• chr6-136191834-C-G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_018945.4(PDE7B):​c.1347C>G​(p.Ser449Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00254 in 1,549,440 control chromosomes in the GnomAD database, including 103 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S449N) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.013 (56 hom., cov: 32)
  • Exomes 𝑓: 0.0014 (47 hom.)
• Consequence: PDE7B NM_018945.4 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.609

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

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0031597614).
• BP6: Variant 6-136191834-C-G is Benign according to our data. Variant chr6-136191834-C-G is described in ClinVar as [Benign]. Clinvar id is 776163.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0132 (2009/152336) while in subpopulation AFR AF= 0.0464 (1927/41564). AF 95% confidence interval is 0.0446. There are 56 homozygotes in gnomad4. There are 943 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 2009 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PDE7B	NM_018945.4	c.1347C>G	p.Ser449Arg	missense_variant	13/13	ENST00000308191.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PDE7B	ENST00000308191.11	c.1347C>G	p.Ser449Arg	missense_variant	13/13	1	NM_018945.4	P1
PDE7B-AS1	ENST00000655618.1	n.82-29486G>C		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.0130 AC: 1983 AN: 152218 Hom.: 52 Cov.: 32

Gnomad AFR AF: 0.0458

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00366

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000132

Gnomad OTH AF: 0.00669

GnomAD3 exomes AF: 0.00329 AC: 507 AN: 154216 Hom.: 12 AF XY: 0.00217 AC XY: 177 AN XY: 81582

Gnomad AFR exome AF: 0.0508

Gnomad AMR exome AF: 0.00243

Gnomad ASJ exome AF: 0.000118

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000175

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000152

Gnomad OTH exome AF: 0.00160

GnomAD4 exome AF: 0.00138 AC: 1933 AN: 1397104 Hom.: 47 Cov.: 31 AF XY: 0.00120 AC XY: 827 AN XY: 689186

Gnomad4 AFR exome AF: 0.0493

Gnomad4 AMR exome AF: 0.00291

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000114

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000705

Gnomad4 OTH exome AF: 0.00301

GnomAD4 genome AF: 0.0132 AC: 2009 AN: 152336 Hom.: 56 Cov.: 32 AF XY: 0.0127 AC XY: 943 AN XY: 74492

Gnomad4 AFR AF: 0.0464

Gnomad4 AMR AF: 0.00366

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000132

Gnomad4 OTH AF: 0.00662

Alfa AF: 0.000664 Hom.: 3

Bravo AF: 0.0152

ESP6500AA AF: 0.0409 AC: 172

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00291 AC: 248

Asia WGS AF: 0.00693 AC: 25 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

May 14, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.62	T
BayesDel_noAF	Benign	-0.62
CADD	Benign	15
DANN	Benign	0.94
DEOGEN2	Benign	0.083	T;T
Eigen	Benign	-0.89
Eigen_PC	Benign	-0.86
FATHMM_MKL	Benign	0.12	N
LIST_S2	Benign	0.49	T;T
MetaRNN	Benign	0.0032	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N;.
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-1.3	N;.
REVEL	Benign	0.13
Sift	Uncertain	0.010	D;.
Sift4G	Benign	0.12	T;D
Polyphen		0.0060	B;B
Vest4		0.067
MutPred		0.25		Loss of phosphorylation at S449 (P = 0.0023);.;
MVP		0.043
MPC		0.37
ClinPred		0.0040	T
GERP RS		0.57
Varity_R		0.084
gMVP		0.39

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: rs77357372; hg19: chr6-136512972;