rs10057110

Positions:

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1BP4_StrongBP6_Very_StrongBA1

The NM_000440.3(PDE6A):c.647A>G(p.Asn216Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00717 in 1,609,690 control chromosomes in the GnomAD database, including 695 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.037 ( 348 hom., cov: 33)

Exomes 𝑓: 0.0040 ( 347 hom. )

Consequence

PDE6A
NM_000440.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 4.83

Variant links:

Genes affected

PDE6A (HGNC:8785): (phosphodiesterase 6A) This gene encodes the cyclic-GMP (cGMP)-specific phosphodiesterase 6A alpha subunit, expressed in cells of the retinal rod outer segment. The phosphodiesterase 6 holoenzyme is a heterotrimer composed of an alpha, beta, and two gamma subunits. cGMP is an important regulator of rod cell membrane current, and its dynamic concentration is established by phosphodiesterase 6A cGMP hydrolysis and guanylate cyclase cGMP synthesis. The protein is a subunit of a key phototransduction enzyme and participates in processes of transmission and amplification of the visual signal. Mutations in this gene have been identified as one cause of autosomal recessive retinitis pigmentosa. [provided by RefSeq, Jul 2008]

PDE6A links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -18 ACMG points.

PM1

In a domain GAF 1 (size 149) in uniprot entity PDE6A_HUMAN there are 8 pathogenic changes around while only 1 benign (89%) in NM_000440.3

BP4

Computational evidence support a benign effect (MetaRNN=0.002271533).

BP6

Variant 5-149934000-T-C is Benign according to our data. Variant chr5-149934000-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 351997.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-149934000-T-C is described in Lovd as [Benign]. Variant chr5-149934000-T-C is described in Lovd as [Likely_benign]. Variant chr5-149934000-T-C is described in Lovd as [Likely_pathogenic].

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.127 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PDE6A	NM_000440.3 linkuse as main transcript	c.647A>G	p.Asn216Ser	missense_variant	3/22	ENST00000255266.10	NP_000431.2
PDE6A	NM_001410788.1 linkuse as main transcript	c.475-2832A>G		intron_variant			NP_001397717.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris
PDE6A	ENST00000255266.10 linkuse as main transcript	c.647A>G	p.Asn216Ser	missense_variant	3/22	1	NM_000440.3	ENSP00000255266	P1
PDE6A	ENST00000508173.5 linkuse as main transcript	n.767A>G		non_coding_transcript_exon_variant	3/20	1
PDE6A	ENST00000613228.1 linkuse as main transcript	c.475-2832A>G		intron_variant		5		ENSP00000478060

Frequencies

GnomAD3 genomes

AF:

0.0373

AC:

5674

AN:

152188

Hom.:

345

Cov.:

show subpopulations

Gnomad AFR

AF:

0.130

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0109

Gnomad ASJ

AF:

0.0115

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000426

Gnomad OTH

AF:

0.0291

GnomAD3 exomes

AF:

0.0101

AC:

2528

AN:

250826

Hom.:

152

AF XY:

0.00771

AC XY:

1045

AN XY:

135586

show subpopulations

Gnomad AFR exome

AF:

0.135

Gnomad AMR exome

AF:

0.00559

Gnomad ASJ exome

AF:

0.0100

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000262

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000229

Gnomad OTH exome

AF:

0.00343

GnomAD4 exome

AF:

0.00402

AC:

5852

AN:

1457384

Hom.:

347

Cov.:

AF XY:

0.00351

AC XY:

2546

AN XY:

725424

show subpopulations

Gnomad4 AFR exome

AF:

0.136

Gnomad4 AMR exome

AF:

0.00602

Gnomad4 ASJ exome

AF:

0.0103

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000244

Gnomad4 FIN exome

AF:

0.0000187

Gnomad4 NFE exome

AF:

0.000187

Gnomad4 OTH exome

AF:

0.00903

GnomAD4 genome

AF:

0.0374

AC:

5692

AN:

152306

Hom.:

348

Cov.:

AF XY:

0.0362

AC XY:

2695

AN XY:

74476

show subpopulations

Gnomad4 AFR

AF:

0.130

Gnomad4 AMR

AF:

0.0108

Gnomad4 ASJ

AF:

0.0115

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000426

Gnomad4 OTH

AF:

0.0288

Alfa

AF:

0.00963

Hom.:

Bravo

AF:

0.0428

ESP6500AA

AF:

0.121

AC:

535

ESP6500EA

AF:

0.000581

AC:

ExAC

AF:

0.0121

AC:

1470

Asia WGS

AF:

0.00606

AC:

AN:

3478

EpiCase

AF:

0.000218

EpiControl

AF:

0.000297

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Retinitis pigmentosa

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.078

BayesDel_addAF

Benign

-0.57

BayesDel_noAF

Benign

-0.47

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.25

Eigen

Benign

-0.059

Eigen_PC

Benign

0.11

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.89

MetaRNN

Benign

0.0023

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.9

MutationTaster

Benign

0.0091

PrimateAI

Uncertain

0.61

PROVEAN

Benign

-2.1

REVEL

Benign

0.11

Sift

Benign

0.23

Sift4G

Benign

0.60

Polyphen

0.080

Vest4

0.084

MPC

0.092

ClinPred

0.038

GERP RS

5.4

Varity_R

0.29

gMVP

0.24

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over